Crystalline microspheres and the process for manufacturing the same

ABSTRACT

The present invention relates to microspheres and compositions comprising a plurality of microspheres, wherein the microspheres are perfectly spherical and have a moisture content less than 1%, and the method of manufacturing the same. The present invention is useful in the manufacture of sustained and modified release active pharmaceutical ingredient (API) microspheres, as a free flowing excipient for mini-tablets and in the manufacture of API dispersions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/638,073 filed Apr. 25, 2012 and U.S. Provisional Application No.61/783,603 filed Mar. 14, 2013, which are hereby incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a composition comprising a plurality ofmicrospheres, wherein the microspheres are perfectly spherical, and themethod of manufacturing the same. The present invention is useful in themanufacture of sustained and modified release active pharmaceuticalingredient (API) microspheres, as a free flowing excipient formini-tablets and in the manufacture of API carrier dispersions.

BACKGROUND OF THE INVENTION

Many commercial pharmaceutical beads are either reactive or insoluble.Reactive beads such as sucrose/starch beads can cause incompatibilitywith active substances and loss of active substance due to the presenceof reducing sugars. Reaction of moisture in beads made withmicrocrystalline cellulose, sucrose, starch or cellulose derivativescontaining beads can cause incompatibility with active substances andloss of active substance due to the presence of moisture. Loss of API ininsoluble beads such as those made with microcrystalline cellulose,starch or cellulose derivatives can result in lack of release of activesubstance or lower extraction yields from the insoluble materials due tothe of insoluble matrixes. Beads made with soluble components such aspolyols can be made with very low moisture content (anhydrous) and canbe made completely soluble.

Current polyol beads are granulated, thus undissolved polyol particles,primary particles, are “glued” together with a binder solution to make asecondary granular structure. This process makes a surface that is onlyas smooth and durable as the starting particle size and as the shapewill allow. The starting material is not completely liquefied as someremain solid in the granulation route approach and thus transitions arepresent. Also for very small spheres the contour of the startingparticle contributes to a lack of having a smooth crevice-free andbump-free surface, thus lacking perfectly shaped solid spheres. Becausethe binder contains a solvent, the wet beads must be dried. Bead dryingcan create internal porosity as well as transition layers of insolublematerials between the undissolved bodies we are calling primaryparticles. Formation of a wet mass is often done using a granulator,followed by an extruder to form a dense packed pellet and then spinningthe pellet on a friction plate into a sphere. Formation can also be doneby a powder layering process on a core particle or bead that needs to belarge enough to maintain separation in the coating process. Thisrequired core and the need to maintain separation restricts the size ofthe bead that can be made. The layering process starts with seed coreupon which insoluble primary particles are deposited and bonded usingthe binder solution. For effective layering the primary particles mustbe small enough (<10 μm for 150 μm sphere) to be formed into areasonably smooth surfaced sphere (<30 μm for 300 μm sphere). Theprimary layering particles and the layer application amount must besmall enough to prevent porosity and/or moisture from being trapped deepin the sphere. Drying during layering process is critical to balanceenough wetness for growth, bead strength and dryness for reducedinterior moisture and prevent vacuoles/residual porosity. A waterinsoluble wicking agent such as MCC aides in the removal of moisture butis insoluble. Final bead size is limited to spheres larger than 100 μmmean size (10 μm primary layering particle size) to allow granularshaping and maintain bead separation (preventing twins) during thelayering process.

Commercially available beads used as cores as API delivery beads inapplications that can survive the temperature/tumbling conditions of theAPI coating and layering process are larger than 100 μm (mean particlediameter). Tablets containing API delivery beads incorporated andcompressed into tablets require smaller size beads if beadcrushing/rupturing of the functional coating on coated bead duringtablet compression is to be avoided. Tablets containing beads are madetypically into swallow tablets to avoid chewing, thus tablet thicknessneeds to be small to allow ease of swallowing. Beads need to becushioned during tablet compression to prevent them from being crushedwith larger bead requiring more cushioning materials. Larger beads placelimitations on the tableting process (slower press speed) andformulation (requires more crushing agents) to create an environmentthat prevents bead fracturing of larger beads. Smaller beads thus allowfor smaller tablets, less cushioning ingredients to be required intablet formulation as well as in the coating layers and higher doseloading of API.

Excipients for very small mini-tablets (<3 mm in tablet diameter),require very small excipient particles for fill/tablet weight control. A1/50 of the diameter of the tablet standard for particle size wouldrequire a particle size mean of 60 μm. Current<90 μm particles ofmicrocrystalline cellulose (MCC) (and milled MCC<90 μm) are used. Thesematerials are not spherical and thus prone to flow issues causing weightuniformity issues, especially at faster tablet press speeds.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides for improvedmicrospheres that can be 100% soluble, perfectly spherical, have auniform surface with limited <2 micron peak to valley roughness, be assmall as 2 μm, be comprised in some embodiments of a single crystalstructure with limited or no internal voids, have low hygroscopicity,and low moisture content of less than 1% weight percentage.

In one embodiment, the present invention relates to improvedmicrospheres comprising a core material, wherein the microsphere isperfectly spherical, and the method of manufacturing the same. In someembodiments, the present invention relates to improved microspherescomprising a core material, wherein the microsphere is perfectlyspherical and has a moisture content less than 1% by weight. In someembodiments, the present invention relates to improved pharmaceuticalmicrospheres comprising a core material, wherein the microsphere isperfectly spherical, has a smooth surface and has a moisture contentless than 1% by weight.

In some embodiments, the present invention relates to improvedmicrospheres comprising a core material, wherein the microsphere isperfectly spherical, has low hygroscopicity, and has a moisture contentless than 1% by weight.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings. For the purpose of illustration the invention,there are shown in the drawings embodiments which are presentlypreferred. It should be understood, however, that the invention can beembodied in different forms and thus should not be construed as beinglimited to the embodiments set forth herein.

FIG. 1 is a photomicrograph of exemplary mannitol microspheres of thepresent invention.

FIG. 2 is a SEM photomicrograph (1000×) of exemplary mannitolmicrospheres of the present invention.

FIG. 3 is a close-up (4000×) micrograph of SEM of exemplary mannitolmicrosphere of the present invention.

FIG. 4 is a micrograph of SEM of exemplary mannitol microspheres of thepresent invention.

FIG. 5 is a graph illustrating the moisture content of exemplarymannitol microspheres of the present invention.

FIGS. 6 (A, B and C) are graphs illustrating the moisture content ofpowdered, granular and spray-dried mannitols.

FIG. 7 is a DSC scan of exemplary mannitol microspheres of the presentinvention.

FIGS. 8 (A and B) are micrographs of SEM of sectioned exemplary mannitolmicrospheres of the present invention.

FIG. 9 is a micrograph of SEM of sectioned exemplary mannitolmicrosphere of the present invention.

FIG. 10 is a micrograph of SEM of Celphere CP-102 microcrystallinecellulose beads (Asahi Kasei Corporation, Tokyo, Japan).

FIG. 11 is a micrograph of SEM of MCell 400 mannitol beads (PharmatransSanaq AG, Allschwil, Switzerland).

FIG. 12 is a micrograph of SEM of Pharm-a-Sphere™ Neutral Pellets (HannsG. Werner GmbH, Tornesch, Germany).

FIG. 13 is a micrograph of SEM of SureSpheres® sugar/starch spheres(Colorcon, West Point, Pa.).

FIG. 14 is micrograph of SEM of Nonpareil-108 mannitol beads (FreundIndustrial Co., Japan).

FIG. 15 is an image of exemplary mannitol microspheres of the presentinvention.

FIG. 16 is an image of MCell 400 mannitol beads (Pharmatrans Sanaq AG,Allschwil, Switzerland).

FIG. 17 is an image of Pharm-a-Sphere™ Neutral Pellets (Hanns G. WernerGmbH, Tornesch, Germany).

FIG. 18 is an image of SureSpheres® sugar/starch spheres (Colorcon, WestPoint, Pa.).

FIG. 19 is an image of Nonpareil-108 mannitol beads (Freund IndustrialCo., Ltd., Tokyo, Japan).

FIG. 20 is a graph illustrating the circularity of exemplary mannitolmicrospheres of the present invention in comparison with variouscommercially available microspheres.

FIG. 21 is a graph illustrating the circularity of exemplary mannitolmicrospheres of the present invention in comparison with variouscommercially available microspheres.

FIG. 22 is a graph illustrating the circularity of exemplary mannitolmicrospheres of the present invention in comparison with Nonpareil-108mannitol beads.

FIG. 23 is a graph illustrating the aspect ratio of exemplary mannitolmicrospheres of the present invention in comparison with variouscommercially available microspheres.

FIG. 24 is a graph illustrating the solidity of exemplary mannitolmicrospheres of the present invention in comparison with variouscommercially available microspheres.

FIG. 25 is a graph illustrating the convexity of exemplary mannitolmicrospheres of the present invention in comparison with variouscommercially available microspheres.

DETAILED DESCRIPTION OF INVENTION

The following detailed description is exemplary and explanatory and isintended to provide further explanation of the invention describedherein. Other advantages, and novel features will be readily apparent tothose skilled in the art from the following detailed description of theinvention.

The present invention is described herein using several definitions, asset forth below and throughout the application.

DEFINITIONS

The term “about” will be understood by persons of ordinary skill in theart and will vary to some extent on the context in which it is used. Ifthere are uses of the term which are not clear to persons of ordinaryskill in the art given the context in which it is used, “about” shallmean up to plus or minus 10% of the particular value.

The terms “solid dosage form,” “tablet,” and “solid preparation” areused synonymously within the context of the present invention. Theseterms should be construed to include a compacted or compressed powdercomposition obtained by compressing or otherwise forming the compositionto form a solid having a defined shape.

The aim of the present invention was to overcome the drawbacks ofexisting commercial beads.

Microsphere refers to a sphere that is from about 1 μm to about 3 mm. Inone embodiment, the present invention relates to a compositioncomprising a plurality of microspheres. A plurality of microspherescomprises from about 50 to about 20,000 microspheres. In someembodiments, a plurality of microspheres comprises from about 50 toabout 15,000 microspheres. In some embodiments, a plurality ofmicrospheres comprises from about 50 to about 10,000 microspheres. Insome embodiments, a plurality of microspheres comprises from about 50 toabout 5,000 microspheres. In some embodiments, a plurality ofmicrospheres comprises from about 100 to about 20,000 microspheres. Insome embodiments, a plurality of microspheres comprises from about 100to about 15,000 microspheres. In some embodiments, a plurality ofmicrospheres comprises from about 100 to about 10,000 microspheres. Insome embodiments, a plurality of microspheres comprises from about 100to about 5,000 microspheres. In some embodiments, a plurality ofmicrospheres comprises from about 100 to about 1,000 microspheres. Insome embodiments, a plurality of microspheres comprises from about 500to about 20,000 microspheres. In some embodiments, a plurality ofmicrospheres comprises from about 500 to about 15,000 microspheres. Insome embodiments, a plurality of microspheres comprises from about 500to about 10,000 microspheres. In some embodiments, a plurality ofmicrospheres comprises from about 500 to about 5,000 microspheres. Insome embodiments, a plurality of microspheres comprises from about 500to about 1,000 microspheres. In some embodiments, a plurality ofmicrospheres comprises greater than about 50 microspheres. In someembodiments, a plurality of microspheres comprises greater than about100 microspheres. In some embodiments, a plurality of microspherescomprises greater than about 200 microspheres. In some embodiments, aplurality of microspheres comprises greater than about 300 microspheres.In some embodiments, a plurality of microspheres comprises greater thanabout 400 microspheres. In some embodiments, a plurality of microspherescomprises greater than about 500 microspheres. In some embodiments, aplurality of microspheres comprises greater than about 750 microspheres.In some embodiments, a plurality of microspheres comprises greater thanabout 1000 microspheres. In some embodiments, a plurality ofmicrospheres comprises greater than about 1250 microspheres. In someembodiments, a plurality of microspheres comprises greater than about1500 microspheres. In some embodiments, a plurality of microspherescomprises greater than about 1750 microspheres. In some embodiments, aplurality of microspheres comprises greater than about 2000microspheres. In some embodiments, a plurality of microspheres comprisesgreater than about 2500 microspheres. In some embodiments, a pluralityof microspheres comprises greater than about 3000 microspheres. In someembodiments, a plurality of microspheres comprises greater than about3500 microspheres. In some embodiments, a plurality of microspherescomprises greater than about 4000 microspheres. In some embodiments, aplurality of microspheres comprises greater than about 4500microspheres. In some embodiments, a plurality of microspheres comprisesgreater than about 5000 microspheres. In some embodiments, a pluralityof microspheres comprises greater than about 7500 microspheres. In someembodiments, a plurality of microspheres comprises greater than about10,000 microspheres. In some embodiments, a plurality of microspherescomprises greater than about 15,000 microspheres.

In some embodiments, the present invention relates to a compositioncomprising a plurality of microspheres, wherein the microspheres haveperfect sphericity. “Perfect sphericity” or “perfectly spherical” meansa circularity as measured by imaging microscopy of greater than about0.90, and an aspect ratio of less than about 1.0. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a circularity greater than about 0.91. In someembodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.92. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.93. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.94. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.95. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.96. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.97. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.98. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have a circularity greater than about 0.99. Insome embodiments, a composition comprises a plurality of microspheres,wherein at least about 40% of microspheres have a circularity greaterthan about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein at least about 50% of microsphereshave a circularity greater than about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein at leastabout 60% of microspheres have a circularity greater than about 0.99. Insome embodiments, a composition comprises a plurality of microspheres,wherein at least about 70% of microspheres have a circularity greaterthan about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein about 20% or less of microsphereshave a circularity greater than about 0.98. Circularity is calculated inaccordance with International Organization for Standardization (ISO)9276-6 (2008).

In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.90. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.91. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.92. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.93. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.94. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.95. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.96. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.97. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.98. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about1.0. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an aspect ratio of about0.90 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.91 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.92 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.93 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.94 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.95 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.96 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.97 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.98 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres have an aspect ratioof about 0.99 or greater. In some embodiments, a composition comprises aplurality of microspheres, wherein at least about 20% of microsphereshave an aspect ratio greater than about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein at leastabout 30% of microspheres have an aspect ratio greater than about 0.99.In some embodiments, a composition comprises a plurality ofmicrospheres, wherein at least about 40% of microspheres have an aspectratio greater than about 0.99. In some embodiments, a compositioncomprises a plurality of microspheres, wherein at least about 50% ofmicrospheres have an aspect ratio greater than about 0.99. In someembodiments, a composition comprises a plurality of microspheres,wherein at least about 60% of microspheres have an aspect ratio greaterthan about 0.99. Aspect Ratio is calculated in accordance withInternational Organization for Standardization (ISO) 9276-6 (2008).

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a convexity ofabout 0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein at least about 30% of the microspheres have aconvexity of about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein at least about 40% of themicrospheres have a convexity of about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein at leastabout 50% of the microspheres have a convexity of about 0.99. In someembodiments, a composition comprises a plurality of microspheres,wherein at least about 60% of the microspheres have a convexity of about0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein at least about 70% of the microspheres have aconvexity of about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein at least about 80% of themicrospheres have a convexity of about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 30% ormore of the microspheres have a convexity of about 0.99. In someembodiments, a composition comprises a plurality of microspheres,wherein about 40% or more of the microspheres have a convexity of about0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 50% or more of the microspheres have aconvexity of about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein about 60% or more of the microsphereshave a convexity of about 0.99. In some embodiments, a compositioncomprises a plurality of microspheres, wherein about 70% or more of themicrospheres have a convexity of about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 80% ormore of the microspheres have a convexity of about 0.99. Convexity Ratiois calculated in accordance with International Organization forStandardization (ISO) 9276-6 (2008).

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a solidity ofabout 0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein at least about 30% of the microspheres have asolidity of about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein at least about 40% of themicrospheres have a solidity of about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein at leastabout 50% of the microspheres have a solidity of about 0.99. In someembodiments, a composition comprises a plurality of microspheres,wherein at least about 60% of the microspheres have a solidity of about0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein at least about 70% of the microspheres have asolidity of about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein at least about 80% of themicrospheres have a solidity of about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein at leastabout 90% of the microspheres have a solidity of about 0.99. In someembodiments, a composition comprises a plurality of microspheres,wherein about 30% or more of the microspheres have a solidity of about0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 40% or more of the microspheres have asolidity of about 0.99. In some embodiments, a composition comprises aplurality of microspheres, wherein about 50% or more of the microsphereshave a solidity of about 0.99. In some embodiments, a compositioncomprises a plurality of microspheres, wherein about 60% or more of themicrospheres have a solidity of about 0.99. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 70% ormore of the microspheres have a solidity of about 0.99. In someembodiments, a composition comprises a plurality of microspheres,wherein about 80% or more of the microspheres have a solidity of about0.99. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 90% or more of the microspheres have asolidity of about 0.99. Solidity Ratio is calculated in accordance withInternational Organization for Standardization (ISO) 9276-6 (2008).

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a mean particlesize from about 2 μm to about 3000 μm in diameter. In some embodimentsof the present invention, a composition comprises a plurality ofmicrospheres, wherein the microspheres have a mean particle size fromabout 2 μm to about 10 μm in diameter. In some embodiments of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have a mean particle size from about 10 μm toabout 20 μm in diameter. In some embodiments of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have a mean particle size from about 10 μm to about 500 μmin diameter. This mean particle size d(0.5) can be anywhere within thisrange based on process conditions chosen. In one embodiment of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have a particle size distribution(d(0.9)/d(0.1)) of about 2.8 or less. In another embodiment of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have a particle size distribution of about 2.7or less. In another embodiment of the present invention, a compositioncomprises a plurality of microspheres, wherein the microspheres have aparticle size distribution of about 2.4 or less. In another embodimentof the present invention, a composition comprises a plurality ofmicrospheres, wherein the microspheres have a particle size distributionof about 2.3 or less. In another embodiment of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have a particle size distribution of about 2.2 or less. Inanother embodiment of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a particle sizedistribution of about 2.1 or less. In another embodiment of the presentinvention, a composition comprises a plurality of microspheres, whereinthe microspheres have a mean particle size distribution of about 2.0 orless. In another embodiment of the present invention, a compositioncomprises a plurality of microspheres, wherein the microspheres have aparticle size distribution of about 1.9 or less. In another embodimentof the present invention, a composition comprises a plurality ofmicrospheres, wherein the microspheres have a particle size distributionof about 1.8 or less. In another embodiment of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have a particle size distribution of about 1.7 or less. Inanother embodiment of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a particle sizedistribution of about 1.6 or less. In another embodiment of the presentinvention, a composition comprises a plurality of microspheres, whereinthe microspheres have a particle size distribution of about 1.5 or less.In another embodiment of the present invention, a composition comprisesa plurality of microspheres, wherein the microspheres have a particlesize distribution of about 1.4 or less. In another embodiment of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have a particle size distribution of about 1.3or less. In another embodiment of the present invention, a compositioncomprises a plurality of microspheres, wherein the microspheres have aparticle size distribution of about 1.2 or less. In some embodiments,the present invention provides for microspheres with a narrow particlesize distribution without a first microsphere size separation step. Insome embodiments, the present invention provides for microspheres with anarrow particle size distribution prior to a first microsphere sizeseparation step.

In some embodiments, the perfect sphericity, perfect solidity, narrowparticle density and lack of pores of the microspheres of the presentinvention create the ability to use size selection to narrowly controlthe effective surface area (ESA) for coating the microspheres per mass.The effective surface area is the surface at the base of the functionalfilm or coating whose thickness for performance is fixed at a minimumand a maximum. Normal for functional films or coating, the thicknessrequired is a film or coating of 10 μm or more. If substantially all ofthe surface of the microsphere is part of the start of the functionalthickness layering it is as if the coating or film is being applied to aflat surface. Thus the build of thickness is uniform and reproducible.Coating lost into pores or needed over risers is not lost if themicrosphere has both a high solidity and a high convexity value. Thesurface area for the weight of beads used in the coating batch can thusbe related directly to bead size and bead size frequency even down to 10μm beads. Factors of shape, bead density, and effective surface lostinto crevices and pores and surface distortions from risers are nolonger factors that affect the relationship of size selection to theeffective surface per batch to be coated. Also particle flow of acircular microsphere at 10 μm is maintained as particles are sphericaland particle to particle contact is at points of contact and thusminimal surface area involved. Also minimal moisture <0.2% generates avery small surface free energy at contact points. In some embodiments,microspheres of the present invention also can be made static free asthe process is a crystallization process, even at the 10 μm level.Maintaining separation is extremely important to prevent agglomerationduring coating and use. Aerodynamics is also uniform based on themicrospheres having uniform shape and density. Submicron crystal ridgesexist even on the 10 μm microsphere thus even though the microsphereappears smooth the surface can be attached to with coating materials.

In some embodiments, the present invention provides for the manufactureof microspheres that have a standardizable surface area, due to theirperfectly spherical shape and their lack of internal porosity. In someembodiments of the present invention, the microsphere lacks internalporosity. In some embodiments, the microsphere lacks internal voids. Avoid is defined as an area in the bead that is not open to the surfaceand thus not a pore. This open area normally filled with air causes thedensity of the particle to be lowered when present. If present, thesepores create particle density variability as their presence is usuallynot uniform. Thus in process using sonic nozzles or using a sizeselection process a specific narrow range of surface area/process weightused will allow coating a much more exact surface area and thevariability of film thickness controlled. Current commercial beads aremade and available in size ranges. In some embodiments, the presentinvention provides for the manufacture and/or sorting of microspheres toprovide microspheres of a standard surface and much more narrowedsurface area range per weight of beads used per batch for coatingprocess. This provides for a uniformly coated microsphere and narrowsthe distribution of coating film thicknesses from batch to batch.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a smoothsurface. A smooth surface with lack of bumps is essential for uniformityin the coating thickness of an API and decreasing the risk of pin holeformations in the coating film. However small ridges in the microspheresurface aide in the adherence of binder or coating solution to thesurface of the microsphere. In one embodiment, a composition comprises aplurality of microspheres, wherein the microspheres have a surface withridges of about 4 μm or less in height. In one embodiment, a compositioncomprises a plurality of microspheres, wherein the microspheres have asurface with ridges of about 3 μm or less in height. In one embodiment,a composition comprises a plurality of microspheres, wherein themicrospheres have a surface with ridges of about 2 μm or less in height.In one embodiment, a composition comprises a plurality of microspheres,wherein the microspheres has a surface with ridges of about 1 μm or lessin height. In one embodiment, a microsphere has a surface with ridges ofabout 0.5 μm or less in height. In one embodiment, a microsphere has asurface with ridges of less than about 4 μm in height. In oneembodiment, a microsphere has a surface with ridges of less than about 3μm in height. In one embodiment, a microsphere has a surface with ridgesof less than about 2 μm in height. In one embodiment, a microsphere hasa surface with ridges of <1 μm in height. In one embodiment, amicrosphere has a surface with ridges of less than about 0.9 μm inheight. In one embodiment, a microsphere has a surface with ridges ofless than about 0.8 μm in height. In one embodiment, a microsphere has asurface with ridges of less than about 0.7 μm in height. In oneembodiment, a microsphere has a surface with ridges of less than about0.6 μm in height. In one embodiment, a microsphere has a surface withridges of less than about 0.5 μm in height. In one embodiment, amicrosphere has a surface with ridges of less than about 0.4 μm inheight. In one embodiment, a microsphere has a surface with ridges ofless than about 0.3 μm in height. In one embodiment, a microsphere has asurface with ridges of less than about 0.2 μm in height. In oneembodiment, a microsphere has a surface with ridges of less than about0.1 μm in height. In one embodiment, a microsphere has a surface withridges of less than about 0.05 μm in height.

In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 1 μm in height.In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.9 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.8 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.7 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.6 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.5 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.4 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.3 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.2 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.1 μm inheight. In some embodiments, a composition comprising a plurality ofmicrospheres does not have any ridges that exceed about 0.05 μm inheight.

In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 80% of the microspheres do not have anyridges that exceed about 1 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 85% ofthe microspheres do not have any ridges that exceed about 1 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 90% of the microspheres do not have anyridges that exceed about 1 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 95% ofthe microspheres do not have any ridges that exceed about 1 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 99% of the microspheres do not have anyridges that exceed about 1 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 80% ofthe microspheres do not have any ridges that exceed about 0.9 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 85% of the microspheres do not have anyridges that exceed about 0.9 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 90% ofthe microspheres do not have any ridges that exceed about 0.9 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 95% of the microspheres do not have anyridges that exceed about 0.9 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 99% ofthe microspheres do not have any ridges that exceed about 0.9 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 80% of the microspheres do not have anyridges that exceed about 0.8 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 85% ofthe microspheres do not have any ridges that exceed about 0.8 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 90% of the microspheres do not have anyridges that exceed about 0.8 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 95% ofthe microspheres do not have any ridges that exceed about 0.8 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 99% of the microspheres do not have anyridges that exceed about 0.8 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 80% ofthe microspheres do not have any ridges that exceed about 0.7 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 85% of the microspheres do not have anyridges that exceed about 0.7 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 90% ofthe microspheres do not have any ridges that exceed about 0.7 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 95% of the microspheres do not have anyridges that exceed about 0.7 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 99% ofthe microspheres do not have any ridges that exceed about 0.7 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 80% of the microspheres do not have anyridges that exceed about 0.6 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 85% ofthe microspheres do not have any ridges that exceed about 0.6 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 90% of the microspheres do not have anyridges that exceed about 0.6 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 95% ofthe microspheres do not have any ridges that exceed about 0.6 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 99% of the microspheres do not have anyridges that exceed about 0.6 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 80% ofthe microspheres do not have any ridges that exceed about 0.5 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 85% of the microspheres do not have anyridges that exceed about 0.5 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 90% ofthe microspheres do not have any ridges that exceed about 0.5 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 95% of the microspheres do not have anyridges that exceed about 0.5 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 99% ofthe microspheres do not have any ridges that exceed about 0.5 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 80% of the microspheres do not have anyridges that exceed about 0.4 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 85% ofthe microspheres do not have any ridges that exceed about 0.4 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 90% of the microspheres do not have anyridges that exceed about 0.4 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 95% ofthe microspheres do not have any ridges that exceed about 0.4 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 99% of the microspheres do not have anyridges that exceed about 0.4 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 80% ofthe microspheres do not have any ridges that exceed about 0.3 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 85% of the microspheres do not have anyridges that exceed about 0.3 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 90% ofthe microspheres do not have any ridges that exceed about 0.3 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 95% of the microspheres do not have anyridges that exceed about 0.3 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 99% ofthe microspheres do not have any ridges that exceed about 0.3 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 80% of the microspheres do not have anyridges that exceed about 0.2 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 85% ofthe microspheres do not have any ridges that exceed about 0.2 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 90% of the microspheres do not have anyridges that exceed about 0.2 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 95% ofthe microspheres do not have any ridges that exceed about 0.2 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 99% of the microspheres do not have anyridges that exceed about 0.2 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 80% ofthe microspheres do not have any ridges that exceed about 0.1 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 85% of the microspheres do not have anyridges that exceed about 0.1 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 90% ofthe microspheres do not have any ridges that exceed about 0.1 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 95% of the microspheres do not have anyridges that exceed about 0.1 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 99% ofthe microspheres do not have any ridges that exceed about 0.1 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 80% of the microspheres do not have anyridges that exceed about 0.05 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 85% ofthe microspheres do not have any ridges that exceed about 0.05 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 90% of the microspheres do not have anyridges that exceed about 0.05 μm in height. In some embodiments, acomposition comprises a plurality of microspheres, wherein about 95% ofthe microspheres do not have any ridges that exceed about 0.05 μm inheight. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein about 99% of the microspheres do not have anyridges that exceed about 0.05 μm in height.

In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the surface of the microsphere is comprised offlat, crystal plates. In some embodiments, a composition comprises aplurality of microspheres, wherein the surface of the microsphere iscomprised of flat, crystal plates that include ridges at one or moreportions of a periphery of the plates. In one embodiment, the ridgesextend radially from the periphery of the plate away from the center orcore of the microsphere. In one embodiment, the ridges extend radiallyaway from the surface to the center or core of the microsphere. In someembodiments, the crystal plates with ridges form shallow ridges of lessthan about 2 μm in height. This allows a film polymer to grip to duringthe early stages of coating and creates a surface with minimum loss offilm material. In some embodiments, the formation of the flat crystalplates is crystals extending to the surface of the microsphere instacked flat crystals forms of either that from growth terminations as astacked group of thin crystals in bundles, each bundle creating asurface plate. In this embodiment, surface ridges are created by crystalplates on the surface that are less than about 1 μm in height. Inanother embodiment, the flat crystal plates on the microsphere surfaceform as crystallization layers in an onion layer growth pattern. In someembodiments, the surface ridges occur at a frequency greater than aboutone per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency greater than abouttwo per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency greater than aboutthree per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency greater than aboutfour per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency greater than aboutfive per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency of about one per μmdistance along the surface of a microsphere. In some embodiments, thesurface ridges occur at a frequency of about two per μm distance alongthe surface of a microsphere. In some embodiments, the surface ridgesoccur at a frequency of about three per μm distance along the surface ofa microsphere. In some embodiments, the surface ridges occur at afrequency of about four per μm distance along the surface of amicrosphere. In some embodiments, the surface ridges occur at afrequency of about five per μm distance along the surface of amicrosphere. In some embodiments, the surface ridges occur at afrequency of about one to about five per μm distance along the surfaceof a microsphere. In some embodiments, the surface ridges occur at afrequency of about two to about five per μm distance along the surfaceof a microsphere. In some embodiments, the surface ridges occur at afrequency of about three to about five per μm distance along the surfaceof a microsphere. In some embodiments, the surface ridges occur at afrequency of about four to about five per μm distance along the surfaceof a microsphere.

In some embodiments, the surface ridges occur at a frequency of lessthan about one per μm distance along the surface of a microsphere. Insome embodiments, the surface ridges occur at a frequency of less thanabout two per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency of less than aboutthree per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency of less than aboutfour per μm distance along the surface of a microsphere. In someembodiments, the surface ridges occur at a frequency of less than aboutfive per μm distance along the surface of a microsphere.

In some embodiments, the flat crystal plates on the surface of themicrosphere are horizontal to a surface of the microsphere and areformed either during the droplet formation due to spinning orientationand/or cooling (surface nucleation orientation) of the droplet to formthe solid microsphere. In some embodiments, the flat, crystal plates onthe surface of the microsphere is formed by the surface of the spinningdisc. In some embodiments, the flat, crystal plates on the microspheresurface are horizontal to a surface of the microsphere. This may bebased on spin roll. In some embodiments, the flat, crystal plates on themicrosphere surface is formed as a molecular orientation on the disc. Insome embodiments, the flat, crystal plates on the microsphere surface isformed from the cooling process. In some embodiments, the flat, crystalplates on the surface of the microsphere formed by the surface of thespinning disk is adjustable based on the surface of the spin disctemperature. In some embodiments, the flat, crystal plates on thesurface of the microsphere formed by the surface of the spinning disk isadjustable based on the spinning speed. In some embodiments, the flat,crystal plates on the surface of the microsphere formed by the surfaceof the spinning disk is adjustable based on the surface of the spin disctemperature and the spinning speed. Although the use of a spinning discis one method of making the microspheres according the inventionsdescribed here, the microspheres described herein are not limited tothose microspheres resulting from the methods disclosed herein. Indeed,the microspheres according to the inventions described herein can bemade by any method that will result in the microspheres according to theinventions described herein.

In contrast, risers, rounded projections from the surface of amicrosphere, cause coating thickness variation by generating local spotsof thin coating or pin holes. If a functional coat must be 10 μm thickand pin holes need to be avoided then the coating over the riser needsto be 10 μm thick, making the coating in other regions required to bethicker. In some embodiments, the surface of the microspheres of thepresent invention has uniform ridges which coating materials can grip tohold onto. In some embodiments, these ridges have a less than about 2 μmdepth and thus contribute little to coating thickness variability. Insome embodiments, a composition comprises a plurality of microspheres,wherein the surface of the microsphere does not have risers.

In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microsphere has vertical or radially rising,very tightly packed crystal formations that are underneath the surfaceof the microsphere. In some embodiments, the vertical or radiallyrising, and very tightly packed crystal formations in the microsphereand the solid center of the microsphere allow the skeletal density ofthe microsphere to approach the true density reported for alphamannitol, and allow for a very narrow control of particle density.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a skeletaldensity of about 1.4595 to about 1.4651 gm/cc by helium pynometry. Insome embodiments, a composition comprises a plurality of microspheres,wherein the microspheres have an average skeletal density of about 1.461gm/cc. This is compared to the true density by x-ray diffraction of apolyol alpha mannitol crystal form found of 1.468 gm/ml. In someembodiments, this develops a bead porosity of(1−(1.468−1.461)/1.468)*100=˜0%. This crystal lattice density matchesthe DSC scan for beads showing a match of crystal energy of alphamannitol and the melting point match to alpha mannitol identifies thesebeads a solid crystal alpha mannitol forms. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about 10% of the skeletaldensity of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −10% and +10% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −9% and +9% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −8% and +8% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −7% and +7% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −6% and +6% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −5% and +5% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −4% and +4% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −3% and +3% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −2% and +2% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −1% and +1% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.9% and +0.9% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.8% and +0.8% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.7% and +0.7% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.6% and +0.6% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.5% and +0.5% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.4% and +0.4% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.3% and +0.3% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.2% and +0.2% of theskeletal density of the microspheres' material. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres have a skeletal density within about −0.1% and +0.1% of theskeletal density of the microspheres' material.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have lowhygroscopicity. In one embodiment, a composition comprises a pluralityof microspheres, wherein the microspheres have a moisture gain of about0.18% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of less than about 2.0% by weight at about90% relative humidity. In one embodiment, a microsphere has moisturegain of less than about 1.9% by weight at about 90% relative humidity.In one embodiment, a microsphere has moisture gain of less than about1.8% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of less than about 1.7% by weight at about90% relative humidity. In one embodiment, a microsphere has moisturegain of less than about 1.6% by weight at about 90% relative humidity.In one embodiment, a microsphere has moisture gain of less than about1.5% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of less than about 1.4% by weight at about90% relative humidity. In one embodiment, a microsphere has moisturegain of less than about 1.3% by weight at about 90% relative humidity.In one embodiment, a microsphere has moisture gain of less than about1.2% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of less than about 1.1% by weight at about90% relative humidity. In one embodiment, a microsphere has moisturegain of less than about 1.0% by weight at about 90% relative humidity.In one embodiment, a microsphere has moisture gain of less than about0.9% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of less than about 0.8% by weight at about90% relative humidity. In one embodiment, a microsphere has moisturegain of less than about 0.7% by weight at about 90% relative humidity.In one embodiment, a microsphere has moisture gain of less than about0.6% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of less than about 0.5% by weight at about90% relative humidity. In one embodiment, a microsphere has moisturegain of less than about 0.4% by weight at about 90% relative humidity.In one embodiment, a microsphere has moisture gain of less than about0.3% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of less than about 0.2% by weight at about90% relative humidity. In one embodiment, a microsphere has moisturegain of less than about 0.1% by weight at about 90% relative humidity.In one embodiment, a microsphere has moisture gain of less than about0.05% by weight at about 90% relative humidity. In one embodiment, amicrosphere has moisture gain of about 0% by weight at about 90%relative humidity.

In another embodiment, a microsphere has a moisture gain of less thanabout 1.00% by weight at about 60% relative humidity. In anotherembodiment, a microsphere has a moisture gain of less than about 0.90%by weight at about 60% relative humidity. In another embodiment, amicrosphere has a moisture gain of less than about 0.80% by weight atabout 60% relative humidity. In another embodiment, a microsphere has amoisture gain of less than about 0.70% by weight at about 60% relativehumidity. In another embodiment, a microsphere has a moisture gain ofless than about 0.60% by weight at about 60% relative humidity. Inanother embodiment, a microsphere has a moisture gain of less than about0.50% by weight at about 60% relative humidity. In another embodiment, amicrosphere has a moisture gain of less than about 0.40% by weight atabout 60% relative humidity. In another embodiment, a microsphere has amoisture gain of less than about 0.30% by weight at about 60% relativehumidity. In another embodiment, a microsphere has a moisture gain ofless than about 0.20% by weight at about 60% relative humidity. Inanother embodiment, a microsphere has a moisture gain of less than about0.10% by weight at about 60% relative humidity. In another embodiment, amicrosphere has a moisture gain of less than about 0.09% by weight atabout 60% relative humidity. In another embodiment, a microsphere has amoisture gain of less than about 0.08% by weight at about 60% relativehumidity. In another embodiment, a microsphere has a moisture gain ofless than about 0.07% by weight at about 60% relative humidity. Inanother embodiment, a microsphere has a moisture gain of less than about0.06% by weight at about 60% relative humidity. In another embodiment, amicrosphere has a moisture gain of less than about 0.05% by weight atabout 60% relative humidity. In another embodiment, a microsphere has amoisture gain of less than about 0.04% by weight at about 60% relativehumidity. In another embodiment, a microsphere has a moisture gain ofless than about 0.03% by weight at about 60% relative humidity. Inanother embodiment, a microsphere has a moisture gain of less than about0.02% by weight at about 60% relative humidity. In another embodiment, amicrosphere has a moisture gain of less than about 0.01% by weight atabout 60% relative humidity. In another embodiment, a microsphere has amoisture gain of about 0% by weight at about 60% relative humidity.Hygroscopicity is measured by Dynamic Vapor Sorption (DVS).

In some embodiments of the present invention, a microsphere has amoisture content of about 2.0% by weight or less. In one embodiment, amicrosphere has a moisture content of about 1.9% by weight or less. Inone embodiment, a microsphere has a moisture content of about 1.8% byweight or less. In one embodiment, a microsphere has a moisture contentof about 1.7% by weight or less. In one embodiment, a microsphere has amoisture content of about 1.6% by weight or less. In one embodiment, amicrosphere has a moisture content of about 1.5% by weight or less. Inone embodiment, a microsphere has a moisture content of about 1.4% byweight or less. In one embodiment, a microsphere has a moisture contentof about 1.3% by weight or less. In one embodiment, a microsphere has amoisture content of about 1.2% by weight or less. In one embodiment, amicrosphere has a moisture content of about 1.1% by weight or less. Inone embodiment, a microsphere has a moisture content of about 1.0% byweight or less. In one embodiment, a microsphere has a moisture contentof about 0.9% by weight or less. In one embodiment, a microsphere has amoisture content of about 0.8% by weight or less. In one embodiment, amicrosphere has a moisture content of about 0.7% by weight or less. Inone embodiment, a microsphere has a moisture content of about 0.6% byweight or less. In one embodiment, a microsphere has a moisture contentof about 0.5% by weight or less. In one embodiment, a microsphere has amoisture content of about 0.4% by weight or less. In one embodiment, amicrosphere has a moisture content of about 0.3% by weight or less. Inone embodiment, a microsphere has a moisture content of about 0.2% byweight or less. In one embodiment, a microsphere has a moisture contentof about 0.1% by weight or less. In one embodiment, a microsphere has amoisture content of about 0.09% by weight or less. In one embodiment, amicrosphere has a moisture content of about 0.08% by weight or less. Inone embodiment, a microsphere has a moisture content of about 0.07% byweight or less. In one embodiment, a microsphere has a moisture contentof about 0.06% by weight or less. In one embodiment, a microsphere has amoisture content of about 0.05% by weight or less. In one embodiment, amicrosphere has a moisture content of about 0.04% by weight or less. Inone embodiment, a microsphere has a moisture content of about 0.03% byweight or less. In one embodiment, a microsphere has a moisture contentof about 0.02% by weight or less. Moisture content is measured by losson drying using Karl Fisher method. Hygroscopicity and moisture contentare important characteristics of microspheres or beads as they mayaffect changes in active pharmaceutical ingredients (APIs), such asamorphous APIs, APIs sensitive to hydration, micronized and freeze-driedAPIs that are sensitive to moisture.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a dissolutionof less than about 2%. In some embodiments of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have a dissolution of less than about 1.5%. In someembodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have a dissolutionof less than about 1%. In some embodiments of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have a dissolution of less than about 0.5%. Dissolution isdetermined as set forth herein in Example 2.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have an oiladsorption capacity of less than about 5%. In some embodiments of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have an oil adsorption capacity of less thanabout 4%. In some embodiments of the present invention, a compositioncomprises a plurality of microspheres, wherein the microspheres have anoil adsorption capacity of less than about 3%. In some embodiments ofthe present invention, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an oil adsorption capacityof less than about 2%. In some embodiments of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have an oil adsorption capacity of less than about 1%. Insome embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have an oiladsorption capacity of less than about 0.9%. In some embodiments of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have an oil adsorption capacity of less thanabout 0.8%. In some embodiments of the present invention, a compositioncomprises a plurality of microspheres, wherein the microspheres have anoil adsorption capacity of less than about 0.7%. In some embodiments ofthe present invention, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an oil adsorption capacityof less than about 0.6%. In some embodiments of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have an oil adsorption capacity of less than about 0.5%. Insome embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have an oiladsorption capacity of less than about 0.4%. In some embodiments of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have an oil adsorption capacity of less thanabout 0.3%. In some embodiments of the present invention, a compositioncomprises a plurality of microspheres, wherein the microspheres have anoil adsorption capacity of less than about 0.2%. In some embodiments ofthe present invention, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an oil adsorption capacityof less than about 0.1%. Oil Adsorption Capacity is determined as setforth herein in Example 2.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres have an actual topredicted surface area ratio of about 5 or less. In some embodiments ofthe present invention, a composition comprises a plurality ofmicrospheres, wherein the microspheres have an actual to predictedsurface area ratio of about 4 or less. In some embodiments of thepresent invention, a composition comprises a plurality of microspheres,wherein the microspheres have an actual to predicted surface area ratioof about 3 or less. In some embodiments of the present invention, acomposition comprises a plurality of microspheres, wherein themicrospheres have an actual to predicted surface area ratio of about 2or less. The actual to predicted surface area ratio is calculated bydividing the actual surface area as determined by Nitrogen GasAdsorption divided by the predicted surface area determined by laserparticle size analysis. These methods and calculations are set forthherein in Example 2.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres are water soluble.Insoluble materials can interfere with the full delivery of an API.Insoluble materials can also become an issue in the formation ofcomplete solutions, plugging needles and filters.

Microsphere Material

In some embodiments, the properties of material candidates for use inthe present invention is a material that melts at less than 250° C. or amaterial that dissolves in, melts with or disperses in the primarymaterial. In some embodiments, the material solidifies from a melt oncooling. In some embodiments, the material solidifies from a melt oncooling, in less than 10 minutes. In some embodiments, cooling can beachieved by chilled or non-chilled air, chilled gases or chilled liquidsin which the material has limited solubility. In some embodiments, thesolidification process forms very thin and parallel depositedcrystalline plates that assimilate with each other into a tight crystalpacking group. In some embodiments, the material that forms themicrosphere is a substance with a trans chemical structure with amolecularly balanced charge distribution and thus a low dielectricconstant (<10). In some embodiments, the material is made up ofpreferred similar sized and preferred uniformly distributed functionalgroups, like hydroxyl groups, that do not hinder greatly the bondformation process on cooling, and can form bonding structures rapidlythrough, as an example, hydrogen bonding almost instantly. In someembodiments, the microsphere material is based on fusion,co-crystallization and/or occlusion of the material into the crystalstructure.

In some embodiments, microspheres of the present invention can becomprised of many different materials including, but not limited to,carbohydrates, polyols, sugars, starches, waxes, polyethylene glycol,cetyl alcohol, stearic acid, fatty acids, fatty acid esters,polyethylene glycol derivatives, materials miscible with thesematerials, or combinations thereof. In some embodiments, themicrospheres do not include cellulose. In some embodiments, themicrospheres do not include lipids. In some embodiments, microspheres ofthe present invention can be comprised of one or more materials thatmelt. In some embodiments, microspheres of the present invention can becomprised of a material that is solid at room temperature. In someembodiments, microspheres of the present invention can be comprised ofone or materials that are crystalline solid at room temperature. In someembodiments, microspheres of the present invention can be comprised ofone or more amorphous materials, such as melts.

In some embodiments, microspheres of the present invention can alsocontain additives including, but not limited to, maltodextrins,microcrystalline cellulose, hydroxypropyl methyl cellulose, methylcellulose, polyvinyl alcohol, sodium CMC, povidone and other vinylderivatives, calcium carbonate, tartaric acid, alginic acid, talc,titanium oxide, color, flavor, sodium lauryl sulfate, ph adjusters,surface active agents or combinations thereof.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres comprise a singlecore material. In another embodiment, composition comprises a pluralityof microspheres, wherein the microspheres comprise a core material, andwherein the core material is a polyol. In another embodiment, acomposition comprises a plurality of microspheres, wherein themicrospheres comprise a core material, and wherein the core material ismannitol. In another embodiment, a composition comprises a plurality ofmicrospheres, wherein the microspheres comprise a core material, andwherein the core material is 100% mannitol. In another embodiment, acomposition comprises a plurality of microspheres, wherein themicrospheres comprise a core material, and wherein the core material issorbitol. In another embodiment, a composition comprises a plurality ofmicrospheres, wherein the microspheres comprise a core material, andwherein the core material is maltitol. In another embodiment, acomposition comprises a plurality of microspheres, wherein themicrospheres comprise a core material, and wherein the core material isisomalt. In another embodiment, a composition comprises a plurality ofmicrospheres, wherein the microspheres comprise a core material, andwherein the core material is erythritol. In another embodiment, acomposition comprises a plurality of microspheres, wherein themicrospheres comprise a core material, and wherein the core material isxylitol. In another embodiment, a composition comprises a plurality ofmicrospheres, wherein the microspheres comprise one or more corematerials. In some embodiments of the present invention, a compositioncomprises a plurality of microspheres, wherein the microspheres have acrystalline structure.

In some embodiments of the present invention, a composition comprises aplurality of microspheres, wherein the microspheres comprise a singlematerial. In another embodiment, a composition comprises a plurality ofmicrospheres, wherein the microspheres comprise a polyol. In anotherembodiment, a composition comprises a plurality of microspheres, whereinthe microspheres comprise mannitol. In another embodiment, a compositioncomprises a plurality of microspheres, wherein the microspheres comprise100% mannitol. In another embodiment, a composition comprises aplurality of microspheres, wherein the microspheres comprise sorbitol.In another embodiment, a composition comprises a plurality ofmicrospheres, wherein the microspheres comprise maltitol. In anotherembodiment, a composition comprises a plurality of microspheres, whereinthe microspheres comprise erythritol. In another embodiment, acomposition comprises a plurality of microspheres, wherein themicrospheres comprise isomalt. In another embodiment, a compositioncomprises a plurality of microspheres, wherein the microspheres comprisexylitol.

In another embodiment, a composition comprises a plurality ofmicrospheres, wherein the microspheres comprise one or more polyols. Inanother embodiment, a composition comprises a plurality of microspheres,wherein the microspheres comprise mannitol and sorbitol. The ratio ofmannitol to sorbitol can vary. In one embodiment, a compositioncomprises a plurality of microspheres, wherein the microspheres comprisemannitol and sorbitol, wherein the mannitol:sorbitol ratio ranges fromabout 99.5:0.5 to about 90:10. In another embodiment, a compositioncomprises a plurality of microspheres, wherein the microspheres comprisemannitol and xylitol. The ratio of mannitol to xylitol can vary. In oneembodiment, a composition comprises a plurality of microspheres, whereinthe microspheres comprise mannitol and xylitol, wherein themannitol:xyltiol ratio ranges from about 99.5:0.5 to about 90:10. Inanother embodiment, a composition comprises a plurality of microspheres,wherein the microspheres comprise mannitol and erythritol. The ratio ofmannitol to erythritol can vary. In one embodiment, a compositioncomprises a plurality of microspheres, wherein the microspheres comprisemannitol and erythritol, wherein the mannitol:erythritol ratio rangesfrom about 99.5:0.5 to about 90:10. In another embodiment, a compositioncomprises a plurality of microspheres, wherein the microspheres comprisemannitol and maltitol. The ratio of mannitol to maltitol can vary. Inone embodiment, a composition comprises a plurality of microspheres,wherein the microspheres comprise mannitol and maltitol, wherein themannitol:maltitol ratio ranges from about 99.5:0.5 to about 90:10. Inanother embodiment, a composition comprises a plurality of microspheres,wherein the microspheres comprise mannitol and isomalt. The ratio ofmannitol to isomalt can vary. In one embodiment, a composition comprisesa plurality of microspheres, wherein the microspheres comprise mannitoland isomalt, wherein the mannitol:isomalt ratio ranges from about99.5:0.5 to about 90:10. In some embodiments, a composition comprises aplurality of microspheres, wherein the microspheres consist of a polyol.In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres consist of two or more polyols.In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres consist of mannitol. In someembodiments, a composition comprises a plurality of microspheres,wherein the microspheres consist of a mannitol and sorbitol. In someembodiments, a composition comprises a plurality of microspheres,wherein the microspheres consist of maltitol. In some embodiments, acomposition comprises a plurality of microspheres, wherein themicrospheres consist of erythritol. In some embodiments, a compositioncomprises a plurality of microspheres, wherein the microspheres consistof xylitol. In some embodiments, a composition comprises a plurality ofmicrospheres, wherein the microspheres consist of isomalt. In someembodiments, a composition comprises a plurality of microspheres,wherein the microspheres consist of mannitol and xylitol. In someembodiments, a composition comprises a plurality of microspheres,wherein the microspheres consist of mannitol and erythritol. In someembodiments, a composition comprises a plurality of microspheres,wherein the microspheres consist of mannitol and maltitol. In someembodiments, a composition comprises a plurality of microspheres,wherein the microspheres consist of mannitol and isomalt.

Methods of Manufacture

In some embodiments, microspheres of the present invention can bemanufactured by various methods. In one embodiment, microspheres can beproduced by prilling (spray chilling) of a melt of core material. Inthis embodiment, a melted material is poured into a heated pressurevessel. The heated pressure vessel is pressurized and the plug valve atthe bottom of the vessel is opened to send the melt thru the spray lineto the nozzle. The spray line is heated if necessary. The nozzle canalso be heated if needed. The prills from the nozzle are collected.

In another embodiment, microspheres of the present invention can be madeby melting a material and dropping the melt onto a spinning spin discfor formation of microspheres. The material is melted. In someembodiments, the material can be melted via pan, oven or use of a powderextruder to melt system, such as is available from Randcastle extruders(RCP-1000) (Cedar Grove, N.J.) to decrease time of material at melt.

In this embodiment, powder is fed in and RPM of unit is set to controlfeed rate of melt. Residence time of melt can be <2 minutes in unit andflow rate is consistent.

In another embodiment, microspheres can be made by melting a material asa powder in the spin disk head assembly (See Gold Metal Cincinnati OhioTornado unit). Once melted, the liquid material is spun into a streamwhich, by centrifugal force, is spread into a thin film and exits thedisk as a ligament that breaks into droplets or exits as droplets. In apreferred embodiment, a surface spinner style disk is preferred with adiameter of 4 inches or more and speed capabilities of from 200 RPM to11,000 RPM. The wheel RPM controls film thickness and thusdroplet/bead/microsphere size. The microspheres are allowed to fall inroom temperature or chilled air to cool. In some embodiments, oncecooled, any twinning or chill damaged beads if present, can be removedwith a bead shape shorter.

In another embodiment, microspheres of the present invention can be madeby using a sonic nozzle system supplied by Brace (Alzenan, Germany)called the Brace Spherisator M. The unit consists of an oven in whichone or two liquid vessels are stored. The oven can be heated up to 200°C. Thus thermal conditions can be maintained on the liquid to 200° C. Insome embodiments, the bottle(s) containing the melt can be pressurized.If the head space is pressurized, the liquid will flow to a nozzle whichis mounted in a sonicator. Both the amplitude and frequency of the sonicenergy can be adjusted. The motion as the liquid exits the nozzle causesthe liquid stream to separate and form drops. In some embodiments, astrobe can be used to see the droplets form. Based on amplitude as agross adjustment and frequency as the finer adjustment, the dropletsrelease as individuals approximately the size the droplet would be as acylinder and surface tension then coverts it to a sphere.

In some embodiments, mannitol alone in a single nozzle or an APIdissolved in or dispersed in the mannitol melt made into microspheresusing this approach produce microspheres either as a pure mannitolmicrosphere or as a mannitol and API dispersion. In some embodiments,phenytoin, carbamazepine and folic acid are examples of APIs that can bedissolved/dispersed in the melt of mannitol at 180° C. The liquid isdelivered from a single sonic nozzle. The nozzle vibrates in an up anddown amplitude at a frequency to produce an individual droplet at thetip. The droplet is allowed to cool as it freely falls to form asolidified microsphere. Cooling can occur at room temperature or in achilled environment. In some embodiments, as a signal nozzle setup usinga 200 μm nozzle at a flow rate of 35 g/min with the amplitude andfrequency set based on a strobe light to maintain droplet formationseparation. Pressure on the vessel is maintained to maintain flow rate.

In some embodiments, a liquid can also be injected in a center nozzle ofa two concentric nozzle setup. In one embodiment, the 100 μm outer andthe 100 μm inner nozzle in the Spherisator M. The material can be amelted API or a non-volatile liquid containing dissolved API or ananosized API suspension or mannitol melt or mannitol melt API solutionor dispersion. The material is delivered under pressure from a vessel inan oven to maintain its temperature needed to maintain the melt. Acoating of a material melt alone or coating of an API dissolved ordispersed in the material melt can form the outer shell.

Applications

The microspheres of the present invention are useful in variousapplications. In one embodiment, the microspheres of the presentinvention are useful in the manufacture of sustained and modifiedrelease beads for dosing active pharmaceutical ingredients (APIs) asmulti-particulate systems. In another embodiment, the microspheres ofthe present invention are useful are carriers for APIs for subsequentmanufacture into tablets. In another embodiment, the microspheres of thepresent invention are useful as a free flowing excipient in themanufacture of mini-tablets. In another embodiment, the microspheres ofthe present invention are useful in the manufacture of API dispersions.

In some embodiments, microspheres of the present invention are useful ascore beads onto which an API is layered either in a suspension or asolution or dry powder alternated with a solution to create a tackysurface and if needed a functional coating also applied. In someembodiments, microspheres of the present invention are useful as corebeads for immediate, modified and/or sustain release active and coatedbeads for inclusion into sachets, capsules and tablet formulations. Insome embodiments, microspheres of the present invention are useful asplacebo beads. In some embodiments, microspheres of the presentinvention are useful as cores for plating of APIs onto by lyophilizationprocess.

In some embodiments of the present invention, microspheres can have asmall particle size. In some embodiments, such microspheres of thepresent invention are useful for sachets and chewable tablets to reducedamage [to the API] during chewing, and to improve the mouthfeel of thetablet. In some embodiments, such microspheres are useful in all dosageforms to reduce final bead size yet allow for high API dose loading. Insome embodiments, such microspheres are useful as they may allow for agreater thickness of API coating and thus a wider range of release rateoptions for use of thicker coatings giving a slower release. In someembodiments, such small microspheres are useful as they may reducelocalized concentration of irritative drug by providing greater surfacearea. In some embodiments, small microspheres are useful as they mayreduce variation in gastric emptying rate and transit time. In someembodiments, small microspheres are useful as they are less susceptibleto dose dumping. In some embodiments, small microspheres are useful asthey disperse more freely in gastrointestinal tract and invariablymaximize API absorption and also reduce peak plasma fluctuation. In someembodiments, small microspheres are useful as they can be used as a freeflowing excipient in mini-tablets.

Compositions

In some embodiments of the present invention, pharmaceuticalcompositions comprise microspheres of the present invention and anactive pharmaceutical ingredient (API). In some embodiments,pharmaceutical compositions comprise a plurality of microspheres andAPI. APIs useful in the present invention may include but are notlimited to those described in the Physician's Desk Reference, 61st ed.Montvale, N.J.: Thomson PDR; 2007, which is incorporated by referenceherein in its entirety. In some embodiments, the API may be presentinside the microsphere. In another embodiment, the API may be present onthe outside of the microsphere. In some embodiments, the microspheres ofthe present invention are useful in combination with standard methods ofAPI incorporation into or onto beads or microspheres.

In some embodiments of the present invention, a blend of powder of acore material and an API can be added to a melt extruder and once meltedwould disperse in melt and discharge as a melt stream either to bepressure atomized or to a spin disc for creation of microspheres. Inanother embodiment, an API can be dissolved in a melted core material.In another embodiment, a second feeder position can be added to atwo-stage melt extruder wherein the melt flowing at a controlled ratebased on RPM of the melt extruder push melt past a powder entry pointwhere a mixture of the API and as an option additional core material orother additives are delivered. The melt and API or API dispersion isthen transferred though a mixing section of the extruder and thendelivered to either the spin disc or to a pressurized atomizer unit.

Conventional Pan System

In some embodiments, microspheres can be coated using a conventional pansystem. The standard coating pan system consists of a circular metal panmounted sat an angle on a stand, the pan is rotated on its horizontalaxis by a motor, the hot air is directed into the pan and onto the bedsurface, and is exhausted by means of ducts positioned through the frontof the pan. Coating solutions are applied by spraying the material onthe bed surface. As coating is applied the coating solution is driedoff. It is common to dust powder mixtures onto wetted beads and dry thebeads in layers. A final color and seal coating is often applied.

The Perforated Coating Pan

In some embodiments, microspheres can be coated using a perforatedcoating pan. Coating pan has perforations along its cylindrical portion.It is driven by a variable speed drive. Supply of hot air and exhaust ofdrying air are arranged to facilitate the coating system throughstainless steel plenums positioned on both sides of the perforatedcoating pan. The pan is enclosed in an airtight housing provided with asuitable door and front glass window. This housing of pan with drive isa stainless steel cabinet accommodating the gearbox, AC variable drive,power panel, hot air unit, exhaust unit and an air fitter.

Liquid spray system is complete with stainless steel liquid storagevessel, variable flow-rate liquid dosing pump, automatic spray gun, andinter-connecting flexible hoses.

The Fluidized Bed Coater

In some embodiments, the Fluid Bed Technology can be used to coatmicrospheres. The Fluid Bed Technology is the more modern approach tocoating beads. It is a very efficient coating technique. The majoradvantage of the Fluid Bed Systems it is a closed system that airsuspends the beads.

In a fluidized bed a coat is introduced to cover the core particlesinside the bed. In the process, a layer is deposited onto the surface offluidized solid particles by spraying with a solution of the coatingmaterial. The fluidizing gas is also use to dry the deposited solution.There is considerable diversity in methods of using fluidized bedtechnology. For e.g. liquids can be applied to fluidized particles in avariety of ways, including top, bottom and tangential spraying. For agiven product, each method can offer markedly different finished productcharacteristics.

Fluidized beds are used for coating because of their high energy andmass transfer. Fluidized beds for film coating can be divided into threegroups: top spray, tangential spray, and bottom-spray equipment.

In the top spray bed, the expansion chamber is lengthened to allowpowder to remain fluidized longer and to move with a higher velocity, sothat agglomeration is minimized. The expansion chamber is conicallyshaped to allow uniform deceleration of air stream. The filter housingis larger and designed to shake the fines back into the bed interruptingfluidization; this reduces agglomeration tendencies. The nozzle ispositioned low in the expansion chamber so that coating material impingeon the fluidized particle a short distance from the nozzle; this reducesdroplet spray drying and provides for longer subsequent drying of thecoated particles. The top spray coater has been used to apply aqueousand organic solvent based film coatings, controlled release coatings.Smaller microspheres in this technique would allow smaller final beadsand/or thicker coatings.

In the bottom spray coating, the Wurster machine employs a cylindricalproduct container with a perforated plate. Inside the container is asecond cylinder (coating partition) with is raised slightly above theperforated plate, centered in the plate below this partition is a spraynozzle used to dispense the coating solution. The perforated plated isdesigned with large holes in the area under the coating partition andsmaller holes in the remainder of the plate, except for one ring oflarge holes at the perimeter. The design allows the core particles to bepneumatically transported upward through the coating partition, anddownward outside this partition. Material passing through coatingpartition receives a layer of coating material, dries in the expansionchamber, and falls back in a semi fluidized state. Material circulatesrapidly in this fashion and receives layer of coating material, dries inthe expansion chamber, and falls back in a semi fluidized state materialcirculates rapidly in this fashion and receives a layer of coating oneach pass through the coating partition. The ring of large holes on theperiphery of perforated plate prevents the accumulation of material atthe container wall. It is used for coating small particles, beads,tablets and capsules.

The tangential spraying system, which is commonly fitted with a rotatingbottom plate, can achieve film quantities nearly as good as the bottomspraying system. The rotation of the plate nicely supports productmovement, so that the required air amount is mainly used for dryingprocess and only to a smaller degree for the product movement.

Fluid Bed Coating

In some embodiments, microspheres can be coated using a fluid bedcoating system. In some embodiments, for microspheres of small sizes thecoating film is used to control the release rate of the API.Microspheres allow the loading of the API in a coating layer first up to1 to 2 mm in diameter followed by the application of the releasecontrolling layer. Thus the small particle diameter of the microsphereadd to API loading capacity and the decreasing particle diameter andthus the specific surface area of a substrate increase dramatically andthe required coating weight gain is not experienced. Drug layering canbe applied more rapidly than the final controlled coating layer.

Rotating Disk Granulation

In some embodiments, microspheres can be coated using granulation.Granulation techniques utilizing centrifugal fluidizing disk that can bemoved up or down to create a variable slit opening between the outerperimeter of the disk and the sidewall of the container. Air is drawninto the product container through the slit under negative pressure.This fluidizes the material along the circumferential surface of theproduct container. At the same time the disk rotates at varying speedsand moves the product by the centrifugal force to the outer portionswhere it is lifted by the fluidizing air stream into the expansionchamber. As the material decelerates, it descends to the center of thedisk and repeats the same sequence.

The fluidization pattern is often described as a spiraling helix orrope-like pattern around the inside of the rotor chamber.

Spray nozzles can be immersed in the bed of fluidized material and sprayapplied in tangential fashion with respect to the particle flow.Microspheres in this process allows for a starting controlled surfaceonto which the coating powder with API can be layered onto and held by aspray solution of coating materials in a rapid layering applicationapproach. Based on the uniformity of both shape and size thesemicrospheres allow for a uniform and rapid gain in weight and maintainseparation readily versus standard crystal seeds currently used andstarter material.

Dosage Forms

The various embodiments of the composition, according to the presentinvention, may be used in a variety of dosage forms including, but notlimited to, chewable tablets, swallow tablets, soft chews includingtablets and soft gel capsules, orally disintegrating tablets, orallydispersible powders, mini-tablets, lozenges, film strips, gums, gels,ointments and creams, tablet inserts (eye, ear, vaginal), suppositories,hard shell capsules, liquid fill capsules, liquid suspensions andsustained release beads.

In some embodiments, the dosage form may include a pharmaceuticallyacceptable ingredient including excipients, orally disintegratingexcipients, including, but not limited to Pharmaburst 500 (SPI Pharma,Inc.); diluents; disintegrants; binders; fillers; bulking agent; organicacid(s); colorants; stabilizers; preservatives; lubricants;glidants/anti-adherants; chelating agents; vehicles; bulking agents;stabilizers; preservatives; tonicity adjusting agents; localanesthetics; pH adjusting agents; antioxidants; osmotic agents;chelating agents; viscosifying agents; wetting agents; emulsifyingagents; acids; sugar alcohol; reducing sugars; non-reducing sugars andthe like used either alone or in combination thereof. In someembodiments, the pharmaceutically acceptable ingredients may includeexcipients, binders, lubricants, sugar alcohols, disintegrating agents,colors, flavors and the like used either alone or combinations thereof.

In some embodiments, a pharmaceutical formulation comprising a pluralityof microspheres may be used in a directly compressible dosage form. Theterm “directly compressible” means that the composition can becompressed to tablet form on standard tableting machines (including, butnot limited to high speed tableting machines) using standard (i.e.,without any specially machined, shaped or coated surfaces) punches anddies, without any significant amount of the composition adhering to thepunches and dies by applying compressive pressure to the composition. Insome embodiments, the compression pressure ranges from 60 MPa to 170 MP.In some embodiments, the compression force ranges from 80 MPa to 150MPa. In some embodiments, the compression pressure is at least 60 MPa.

The term “pharmaceutical formulation” as used herein refers toformulations containing the composition of the present invention incombination with carriers or excipients suited to a selected drugdelivery platform, e.g., a capsule, an orally dispersible formulation,an effervescent formulation, a chewable tablet, a lozenge, a hard orswallow tablet, or the like.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for oral drug administration, and include any such materialsknown in the art, e.g., diluents, binders, granulating agents,disintegrants, lubricating agents, colorants, flavoring agents, and thelike.

In some embodiments, various types of pharmaceutical formulations may beprepared using the presently disclosed microspheres and compositions,including powders, chewable tablets, orally dissolving tablets,effervescent formulations, and liquid dispersions. For solidformulations such as powders, chewable tablets, orally dissolvingtablets and effervescent formulations, conventional carriers, excipientsand additives can be employed, including diluents, binders, granulatingagents, disintegrants, flavoring additives, and the like. Examples ofthe normally employed excipients include pharmaceutical grades ofmannitol, lactose, starch, and the like. Liquid pharmaceuticalcompositions containing the present microspheres will generally beprepared by dispersing or suspending the microcapsules in a non-aqueouscarrier which does not cause release of the drug, or else by dispersingthe microspheres or composition in an aqueous carrier immediately priorto administration to the patient. In some embodiments, the microspheresor composition may be provided as a free-flowing particulate material,as in a sachet or other suitable package, and such a particulatematerial may be dispersed in an aqueous carrier. These solid or liquidformulations may contain any amount of the microsphere or compositionneeded to provide the desired amount of the active ingredient containedin the microsphere or composition. In some embodiments, amounts ofmicrospheres or composition on the order of about 10 wt. % to about 95wt. % of the dosage form may be used. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart.

It will be apparent to one of skill in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention. Thus, it is intended that the present invention cover themodifications and variations of the present invention provided they comewithin the scope of the appended claims and their equivalents.

EXAMPLES

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.Throughout the specification, any and all referenced publicly availabledocuments, including but not limited to a U.S. patent, are specificallyincorporated by reference.

Example 1

Mannitol (EP) (Shandong Tianli Pharmaceutical Ltd., Guangzhou, China)and mannitol/sorbitol (2.3%) (sorbitol, Roquette, Keokuk, Iowa)microspheres were produced by prilling (spray chilling) of a melt of thepolyols in a stainless steel 2 quart sauce pan. The melted polyol waspoured into a heated pressure vessel that was heated by electrical heatbands. The heated pressure vessel was pressurized to 50 psig and theplug valve at the bottom of the vessel was opened to send the mannitolthru the spray line to the nozzle. The spray line was heated byelectrical heat tape. The nozzle was heated with a propane torch priorto opening the valve. The prills from the nozzle (Spraying Systems 6501)were collected on plastic and bagged for evaluation. Microspheresparticle size distribution was determined by Malvern Mastersizer Laseranalysis (Malvern, Pa.). Table 1 shows the particle size distribution ofthe microspheres. Microsphere diameters were in the 250 μm mean rangewith a broad distribution (d(0.1)=124 and d(0.9)=473 um or 473/124=3.8to 1 distribution ratio and d(0.1)=204 and d(0.9)=598 um or 598/204=2.9to 1 distribution ratio. FIG. 1 shows a photomicrograph of themicrospheres demonstrating a total smooth glass-like surface of themicrospheres. (Carl Zeiss Microscope Model Axio Vert.A1 (Oberkochen,Germany)).

TABLE 1 Particle size distribution Sample d(0.1) d(0.5) D(0.9) PSD RatioSample 1 124 250.6 473 3.8 (Mannitol) Sample 2 122 261.6 494 4.0(Mannitol) Sample 3 164 323 567 3.45 (Mannitol/Sorbitol) Sample 4 96 225451 4.7 (Mannitol/Sorbitol)

Example 2

Mannitol EP (Shandong Tianli Pharmaceutical Ltd., Guangzhou, China),mannitol/sorbitol (2.3%) (sorbitol, Roquette, Keokuk, Iowa) andmannitol/polysorbate 80 (Unichema, New Castle, Del.) microspheres weremade by melting polyol and dropping melt to spin disc for formation ofmicrospheres. Mannitol is melted in pan or oven at 10° C. above itsmelting point for mannitol a temperature higher than 176° C. Oncemelted, the liquid mannitol is spun into a stream which, by centrifugalforce, is spread into a thin film and exits the disk as a ligament thatbreaks into droplets or exits as droplets. Surface spinner style disk ispreferred with a diameter of 4 inches or more and speed capabilities offrom 500 RPM to 11,000 RPM. Wheel RPM controls film thickness and thusdroplet/bead size. Microspheres are allowed to fall at least 8 feet inroom temperature or chilled air to congeal. Once congealed a coarsescreen can be used to complete cooling and maintain separation. Anytwinning or chill damaged microspheres are removed with a bead shapeshorter.

Microspheres were analyzed for particle size using Malvern Mastersizer.Table 2 shows the particle size distribution (PSD) of the microspheres.

Scanning electron microscopy (SEM) was performed on exemplary mannitolmicrospheres. FIG. 2 is a close up (1,000× magnification) micrograph ofSEM (with 10 μm measurement bar) of the mannitol microspheres made bythis process. Note the surface flat, crystal plates with ridges present,the perfect circularity and sphericity and the lack of crevices andrisers. The frequency of the ridges seen in FIG. 2 are greater thanabout one per μm of distance along a surface of the microsphere(i.e., >about 10 per the length of the 10 μm bar as shown in FIG. 2along a surface of the microsphere). FIG. 2 shows that all sizes ofparticles have similar ridge texturing. FIG. 3 is a close up (4,000×magnification) micrograph of SEM (with 5 μm measurement bar) of thesurface of the center mannitol microsphere shown in FIG. 2. Note theflat crystal plates that form ridges on the surface of the microsphere.The flat crystal plates orient in a horizontal direction either duringthe droplet formation (due to spinning orientation) and/or cooling(surface nucleation orientation) of the droplet to form the solidmicrosphere. The ridges are less than 1 μm in height. The frequency ofthe ridges as seen in FIG. 3 are greater than about one per μm ofdistance along a surface of the microsphere (i.e., >about 5 per thelength of the 5 μm bar as shown in FIG. 3 along a surface of themicrosphere).

FIG. 4 is a micrograph of SEM, which shows the size distribution ofmannitol microspheres available with this process and the ability toachieve microspheres at sizes down to about 10 μm and smaller. Note inthis figure, the uniformity of shape and circularity/sphericalness evenat and down to the 10 μm level. FIG. 4 also shows that all sizes of themicrospheres contain a similar very shallow but rough surface based onthese flat crystal plate ridges being present and none, in thisembodiment, are glass surface smooth.

TABLE 2 Particle size distribution Sample d(0.1) d(0.5) D(0.9) PSD Ratio133.6 211.7 297.2 2.2 Run 1-Mannitol EP Disc Speed: 2000 RPM Flow Rate:110 gm/min 120 223 395 3.3 Run 2-Mannitol EP Disc Speed: 1500 RPM FlowRate: 110 gm/min 126 216 354 2.8 Run 3-Mannitol EP Disc Speed: 1250 RPMFlow Rate: 110 gm/min 162 273 456 2.8 Run 4-Mannitol EP Disc Speed: 1000RPM Flow Rate: 110 gm/min 226 407 672 2.97 Run 5-Mannitol EP Disc Speed:750 RPM Flow Rate: 110 gm/min 299 499 777 2.6 Run 6-Mannitol EP DiscSpeed: 2000 RPM Flow Rate: 49 gm/min Run 7-Mannitol EP Disc Speed: 1500RPM Flow Rate: 49 gm/min 178 303 494 2.8 Run 8-Mannitol EP Disc Speed:1250 RPM Flow Rate: 49 gm/min 221 373 602 2.7 Run 9-Mannitol EP DiscSpeed: 1500 RPM Flow Rate: 110 gm/min 146 299 531 3.6 Run 10-Mannitol EPDisc Speed: 1500 RPM Flow Rate: 49 gm/min 178 303 494 2.8 Run11-Mannitol EP Disc Speed: 1500 RPM Flow Rate: 110 gm/min 248 447 7302.9 Run 12-Mannitol EP Disc Speed: 1500 RPM Flow Rate: 49 gm/min 162 277469 3.1 Run 13-Mannitol EP Disc Speed: 1500 RPM Flow Rate: 200 gm/min127 252 478 3.8 Run 14-Mannitol EP Disc Speed: 1500 RPM Flow Rate: 163gm/min 150 310 564 3.76 Run 1-Mannitol EP Disc Speed: 11000 RPM FlowRate: 110 gm/min (10/7) 29 57 105 3.6 Run 2-Mannitol EP Disc Speed:11000 RPM Flow Rate: 163 gm/min (10/7) 27 58 117 4.3 Run 3-Mannitol EPDisc Speed: 11000 RPM Flow Rate: 200 gm/min (10/7) 29 63 123 4.24 Run4-Mannitol EP Disc Speed: 5000 RPM Flow Rate: 200 gm/min (10/7) 33 66129 3.9 Run 5-Mannitol/ Disc Speed: 5000 RPM Flow Rate: 200 gm/minSorbitol 35 74 138 3.9 Run 6-Mannitol/ Disc Speed: 11000 RPM Flow Rate:300 gm/min Sorbitol 24 62 130 5.4 Run 7-Mannitol w/ Disc Speed: 5000 RPMFlow Rate: 200 gm/min polysorbate 80 35 74 138 2.5

Karl Fisher Moisture (USP)

Approximately 1.0 g of the mannitol EP microspheres, ColorconSureSpheres® sugar/starch spheres (Colorcon, West Point, Pa.), andWerner Pharm-a-Sphere™ Neutral Pellets (Hanns G. Werner GmbH, Tornesch,Germany) were analyzed for moisture content using in the Karl Fishermethod described in US Pharmacopeia (USP) 26. Table 3 shows the moisturecontent of the mannitol microspheres, SureSpheres, and Pharm-a-Spheres.

TABLE 3 Moisture content of mannitol microsphere vs. commercial beadsProduct Mass (g) Titrant (ml) Water (%) SureSphere 1.0053 2.560 1.32Pharm-a-Sphere 1.0032 1.578 0.81 Neutral Pellets Mannitol (USP) 0.99880.184 0.1 Microspheres (10/7/1-6) Mannitol (EP) 1.0087 0.036 0.02Microspheres (10-6-9)

Dynamic Vapor Sorption

0.2 g of the mannitol EP microsphere was analyzed on an AquaDyneInstrument of the Quantachrome (Quantachrome Instruments Palm BeachFla.) using the aquaWin—Data Acquisition and Reduction to measuredynamic vapor sorption. FIG. 5 shows the hygroscopicity of mannitolmicrospheres. Results show that mannitol microspheres are extremelynon-hygroscopic at normal process conditions of 60% relative humidity(RH) as weight gain is less than 0.05%. Results also show a lack ofmoisture adsorbing pore sizes as beads even at 90% RH gained less than0.2% moisture.

In order to compare the hygroscopicity of the mannitol microspheres toother forms of mannitol, powdered (Mannogem® powder, Lot #121101399F,SPI Pharma, Inc.; Pearlitol 50C, Lot # KVKRN, Roquette Freres), granular(Mannogem granular, Lot #121101116G, SPI Pharma, Inc.; Pearlitol 400DC,Lot # E592J, Roquette Freres), and sprayed-dried mannitol (Mannogem EZ,Lot #121101324, SPI Pharma, Inc.; Pearlitol 200 SD, Lot #E983G, RoquetteFreres) products were submitted to Quantachrome for Dynamic VaporSorption (DVS) analysis.

The adsorption profiles for Mannogem powder and Pearlitol 50c arecompared in FIG. 6A. The profile for Mannogem powder shows that itbegins to adsorb more moisture at around 62% relative humidity. Inaddition, the Mannogem powder reaches a higher adsorption at 95% RH.

The adsorption profiles for Mannogem granular and Pearlitol 400DC arecompared in FIG. 6B. Similar to the Mannogem powder profile, theMannogem granular shows a higher moisture adsorption at around 55%relative humidity. The Mannogem granular appears to stop adsorbingmoisture at around 86% RH.

The adsorption profiles for Mannogem spray dried and Pearlitol 200SD arecompared in FIG. 6C. The profile for Mannogem spray dried shows that theSPI product has a much lower adsorption than the Pearlitol 200SD. ThePearlitol increases in adsorption at around 60% relative humidity. Inaddition, the Pearlitol 200SD has a much higher adsorption at thehighest RH values.

None of the above adsorption profiles for the powder, granular andspray-dried mannitol-based commercial products are below 0.2% moisturecontent at 95% RH. As seen in FIG. 4, the mannitol microspheres of thepresent invention have a less than 0.2% moisture weight gain at 95% RHcompared to over 1.5% for the Mannogem EZ which was the best performeramongst powder, granular and spray dried products tested.

Mannitol microspheres was measured by differential scanning calorimetry(DSC) using a Thermal Analysis (New Castel, Del.) DSC Q2000 instrumentwith a version V23.5 data acquisition system at 10° C. per minute fromroom temperature to 300° C. FIG. 7 shows DSC scan of mannitolmicrosphere at alpha mannitol melt point of 166° C. and with heat offusion at 302 J/gm. From Burger*, alpha mannitol heat of fusion is 285.3J/gm. Thus bond energy/gm is equal to or more than alpha mannitol. Betais 293 J/gm as reported by Burger*. This demonstrates that the bondenergy in the crystal lattice is equal to or less than that of themicrosphere and thus the bead is 100% crystalline with limited to noamorphous regions. *Artur Burger, Jan-Olav Henck, Silvia Hetz, JudithRollinger, Andrea Weissnicht, Hemma Stottner. Journal of PharmaceuticalScience 89.4 (2000): 457-468.

Skeletal Density

Mannitol EP microspheres and Nonpareil-108 beads (Freund Industrial Co.,Japan) were analyzed for skeletal density using an Ultrapyc 1200e V4.02of Quantachrome Corporation (Palm Beach, Fla.). Table 4 shows theskeletal density of mannitol microspheres. Table 5 shows the skeletaldensity of Nonpareil-108 beads.

TABLE 4 Skeletal density of mannitol microspheres by helium pycnometryRun Volume (cc) Density (g/cc) 1 0.8655 1.4651 2 0.8674 1.4620 3 0.86741.4620 4 0.8680 1.4609 5 0.8684 1.4602 6 0.8692 1.4590 7 0.8688 1.4595Average Density: 1.461 g/cc

TABLE 5 Skeletal density of Nonpareil-108 beads by helium pycnometry RunVolume (cc) Density (g/cc) 1 0.3947 1.4547 2 0.3947 1.4549 3 0.39461.4552 4 0.3946 1.4552 5 0.3945 1.4554

The closeness of the helium pycnometry skeletal density to the truedensity of alpha mannitol at 1.468 gm/cm⁻³ (Burger et al. *) versus1.4590 to 1.4651 for samples indicates microspheres are solid structuresand substantially lack interior voids/porosity. Whereas the skeletaldensity of NP-108 is 1.4552, which indicates that it is not a purepolymorphic structure.

Mannitol Crystalline Density Beta Alpha Density gm/cm⁻³ 1.49 1.468

Scanning electron microscopy (SEM) was performed on sectioned mannitolmicrospheres to examine the interior structure of the microspheres.FIGS. 8 A and B are micrographs of the SEMs showing that the mannitolmicrosphere is solid and lacks interior voids. FIG. 9 is a micrograph ofthe SEM shows that there is present a thin layered surface area. FIG. 9also shows vertical or radially rising, very tightly packed crystalformations that are underneath this upper layered surface structure.This upper layer of tightly packed crystal plates with ridges formroughened shallow ridges <2 μm in height that allow a film polymer togrip to the surface with minimal loss into depression depths during theearly stages of coating. The extremely shallow depth of the ridgescreates a surface that allows for a minimum loss of film materialdeposits needed for a functional film. This very dense inner layer andthe solid center of the bead allow the skeletal density of themicrosphere to approach the true density reported for Alpha Mannitol,and allow for a very narrow control of particle density.

SEM was also performed on current commercial microspheres/beads:Celphere CP-102 microcrystalline cellulose beads (Asahi KaseiCorporation, Tokyo, Japan), MCell 400 mannitol beads (Pharmatrans SanaqAG, Allschwil, Switzerland), Pharm-a-Sphere™ Neutral Pellets (Hanns G.Werner GmbH, Tornesch, Germany), SureSpheres® sugar/starch spheres(Colorcon, West Point, Pa.), Nonpareil-108 (NP-108) mannitol beads(Freund Industrial Co., Japan). FIG. 10 is a micrograph of SEM ofCelphere CP-102 microcrystalline cellulose beads, which have a smoothpolymer type surface with some risers and convexed indentations presentbut limited cracks and fissures. The common watermelon or potato shapeis apparent which would cause these particles to wabble in flow versusroll and also then to segregate on a shape basis. FIG. 11 is amicrograph of SEM of MCell 400 mannitol beads, which shows the imperfectspherical nature of the beads, as well as the presence of convexity andlack of solidity caused by very deep fissures and risers. Also the beadstructure is a fusion of multiple particles in a granular form verses asingular crystal body. FIG. 12 is a micrograph of SEM of Pharm-a-Sphereneutral pellets, which shows a lack of the deep crevices seen in theMCell beads but shows what appears to be a single grown particle withoutappearance of agglomeration. FIG. 13 is a micrograph of SEM ofSureSpheres, which shows a non-spherical appearance, solid body and alack of crevices. FIG. 14 is a micrograph of SEM of NP-108 beads. Therolling motion used to make the NP-108 beads is obvious in the linearrisers that curve in a spiral manner on the surface of the bead. Theshape is round to cantaloupe to egg-shaped. Lack watermelon type shapes.Surface has crater type dish depression rather than ridges. The edges ofthese ridges are smoothed out based on the process of wet rolling duringthe manufacturing. Based on non-spherical shapes created in the processof manufacture, which appears to be a rolling/tumbling process thismaterial will tend to segregate during the coating process. Presence ofthe cantaloupe to egg-shapes will create both shape motion variation andshape and size segregation during in the coating process. Mannospheremicrospheres of the present invention are substantially all sphericaland will not have the shape motion variation or shape segregation issueas great as NP-108 beads. For Mannospheres, microsphere size wouldcontrol particle distribution during coating process as shape is morespherical.

Circularity

Characterization of the sphericity or circularity of microspheres wasconducted by Particle Technology Labs (Downers Grove, Ill., USA).Automated microscopy and image analysis techniques (Malvern MorphologiG3S automated particle image analysis system, Malvern Instruments Inc.,USA) were used to characterize the morphology of microspheres of thepresent invention, and to compare to current commercially availablemicrospheres, and to calculate mean circularity, aspect ratio, convexityand solidity of each. FIGS. 15-19 are the images generated for each. Thenumber below the microsphere in FIGS. 15-18 is the random selection ofmicrosphere the instrument used to print the silhouettes. FIG. 15 is animage of exemplary mannitol microspheres of the present invention. Notethe only thing seen out of round in the silhouette picture is particleswith point appendages/attachments called twinings These types of twiningparticles can be prevented or removed after manufacture to create aproduct of perfect spherical shape. FIG. 16 is an image of MCell 400mannitol beads (Pharmatrans Sanaq AG, Allschwil, Switzerland), whichshows their non-perfect spherical nature, the presence of risers and ofconvexed surfaces. FIG. 17 is an image of Pharm-a-Sphere™ NeutralPellets (Hanns G. Werner GmbH, Tornesch, Germany), which shows they arenon-perfect spheres with risers. FIG. 18 is an image of SureSpheres®sugar/starch spheres (Colorcon, West Point, Pa.), which shows theirnon-spherical appearance. FIG. 19 is an image of Nonpareil-108 mannitolbeads (Freund Industrial Co., Ltd., Tokyo, Japan), which shows a largeamount of finer particles, and they appear to have crevices and riserson the surface. Many of the beads/particles lack spherical shape andgenerate a potato shape, which is characteristic of the granulation andgrowth by layering process.

The circularity of each of the various microspheres was determined.Circularity is a measurement of the calculated peripheral length of acircle of the same silhouetted area of a particle's blocking a lightsource/the particle's actual peripheral length with values in the rangefrom 0-1. A perfect circle has circularity of roundness 1.0, while aneedle-shaped object has roundness close to 0. Table 6 shows thecircularity of various shapes (Image Analysis: Evaluating Particle Shapeby Horiba Particles on Jul. 7, 2011 by Jeff Bodycomb www.horiba.com).

TABLE 6 Circularity of various shapes Shape

Circularity 1.0 0.886 0.777 0.660 0.509 0.4The circularity—is typically determined using the equation:

Circularity=2(π area)̂0.5/P

where A is the measured area and P is the perimeter length of themicrospheres. Circularity is calculated in accordance with InternationalOrganization for Standardization (ISO) 9276-6 (2008).

In this depiction, the 0.886 circularity relates to the shape of asquare or in three dimensions a cube and indicates the particle hassharper point or corners in its surface structure and would tumbleverses roll. Tumbling is damaging to coating and causes segregation onshape and sharp edges cause issues in both coating stress and coatingdistribution, resulting in uneven coating thickness and coat crackingSharp edges on the bead surface can also break off and becomeincorporated in the coating and cause cracking and early release issues.Sharp edges can also add stress to the coating as it dries and cause thecoating to crack. The presence of cracking can lead to the need to usemore plasticizer which causes the coated particle to be tackier. Table 7shows the circularity of the various microspheres tested.

TABLE 7 Circularity of various microspheres Circu- Circu- CircularityCircularity larity larity % % <0.99 % <0.98 % <0.97 MaterialMaker >0.99 >0.98 >0.97 >0.96 Mannospheres SPI Pharma 74%  9.42%  4.97% 4.93% SureSpheres Colorcon  0%  0.36% 14.34% 27.06% 20/25 MCell 400 TPharmatrans  0%    0%  0.43%  0.97% Sanaq AG Pharm-a- Hanns  0%    0%   0%  0.53% Spheres Werner GmbH NP-108 Freund  0% 32.85% 32.85% 13.97%Industrial Co.

FIG. 20 is a graph of the circularity at 0.95 of the variousmicrospheres examined. FIG. 21 is a graph of the circularity at 0.99 ofthe various microspheres examined. FIG. 22 is a graph of the circularityat 0.99 of the microspheres of the present invention and the NP-108(Freund Industrial Co., Japan). The results show that >95% of themannitol microspheres of the present invention (Mannosphere) are perfectcircles at greater than a circularity of 0.99, with perfectionbeing >0.995. Also note the difference in distribution between thevarious commercial materials. The values below 0.9 mixed in with valuesabove 0.95 will lead to a segregation issue based on the fact that somemicrospheres will tumble while others will roll. The data on circularitydemonstrates that 96.8% of the mannitol microspheres of the presentinvention have a greater than 0.95 circularity rating, while 0% of theMCell microspheres have a circularity of greater than 0.985. Thereforethey would be expected to tumble more than roll. Likewise, 0% of thePharm-a-Spheres have a circularity of greater than 0.975, and thereforethey would be expected to tumble and bounce more than roll. Likewise, 0%of the Surespheres have a circularity of greater than 0.99 with 72.7%greater than 0.95, thus some of these beads will roll but some willtumble more than roll.

Aspect Ratio

The aspect ratio of each of the microspheres was also determined. Aspectratio is defined as the ratio of the length of a sphere divided by thewidth, with the microspheres being considered circular (spherical) ifthe aspect ratio lies between 0.95 and 1.00. Table 8 shows the aspectratios of various shapes (Image Analysis: Evaluating Particle Shape byHoriba Particles on Jul. 7, 2011 by Jeff Bodycomb www.horiba.com). Theaspect ratio is sensitive to how isometric the particle is. Particleswith a high aspect ratio not only tumble but they tend to lodge in porespaces in the coating bed and bounce as they tumble. This is a measureof rod, plate or needle-like characteristics of a particle.

TABLE 8 Aspect ratio of various shapes Shape

Circularity 1.0 0.886 0.777 0.660 0.509 0.4 Aspect Factor 1.0 1.0 1.00.25 0.10 0.05 Aspect Ratio 1:1 1:1 1:1 1:4 1:10 1:20

Aspect ratio is the ratio of the shortest diameter of particle to thelongest diameter of a particle. Aspect ratio is calculated in accordancewith International Organization for Standardization (ISO) 9276-6 (2008).Feret measured diameters as parallel lines brought in to touch particleat any angle. Thus it is the shortest separation of these lines divideby the longest separation.

Aspect Ratio is peak height but not crevice biased. The closer theaspect ratio is to 1 the more free rolling, less tumbling, mechanicallyinterlocking and bouncing is a particle will it flows during the processof coating.

Table 9 and Table 10 show the aspect ratios of the microspheres testedand FIG. 23 is a graph of the aspect ratios of the various microspherestested. The results show a large disparity between other commerciallyavailable beads/microspheres and the microspheres of the presentinvention. With 89.8% of the microspheres of the present invention(Mannospheres) greater than 0.95 in aspect ratio and all the other beadsless than 12% have aspect ratio of greater than 0.95. Also note thedistribution of aspect ratios in the samples. The closer the aspectratio is to 1.0, the more free rolling, less tumbling, mechanicallyinter locking and bouncing is a particle will it flows during theprocess of coating. Note the large disparity between other commerciallyavailable beads and the beads of this invention. Motion patterns changebased on aspect ratio thus a narrow distribution of aspect ratio tend toflow the same with less segregating. A broad aspect shape range tends tosegregate based on its motion patterns being different. Thus the broaderthe aspect ratio or factor the greater the segregation risk. Coatinguniformity requires control of the surface being coated in the spraypattern called the spray flux, appearance of the microsphere in the areaof the spray. Mixing of spherical particles of equal size with othershapes such as watermelon, oblong, flakes, and/or rods will causechanges in flux rate of a microsphere. This can occur by submersion ofthe particles under the bed below the surface being sprayed on, movementof the particles based on its shape more rapidly/slowly thought thespray zone or movement of the particle based on its shape alone intoregions/area where spray is not being applied or applied as fast.

TABLE 9 Aspect ratio of the microspheres tested Aspect Aspect AspectAspect ratio % > ratio % < ratio % < ratio % < Material Maker Lot 0.950.95 > 0.90 0.90 > 0.85 0.85 > 0.80 Mannospheres SPI Pharma 10/7/11-489.83% 5.00% 3.15% 1.92% SureSpheres Colorcon ST502051 8.41% 21.11%23.61% 18.43% 20/25 MCell 400 T Pharmatrans 5100824001 5.14% 12.65%15.76% 17.26% Sanaq AG Pharm-a- Hanns Werner 08010002 8.47% 14.74%20.46% 20.25% Spheres GmbH NP-108 Freund 109C-26 19.93% 31.88% 20.65%9.96% Corporation

TABLE 10 Aspect ratio of the microspheres tested Aspect Aspect AspectAspect Aspect Aspect ratio % > ratio % < ratio % < ratio % < ratio % <ratio % < Material Maker 0.99 0.99 > 0.98 0.98 > 0.97 0.97 > 0.96 0.96 >0.95 0.95 Mannospheres SPI Pharma 64.45% 16.10% 4.55% 2.60% 1.82% 10.48%SureSpheres Colorcon 1.07% 1.43% 1.43% 1.97% 2.50% 91.59% 20/25 MCell400 T Pharmatrans 0.75% 0.64% 0.96% 1.07% 1.71% 94.86% Sanaq AGPharmaspheres Hanns 1.67% 1.46% 1.48% 1.74% 2.13% 91.53% Werner GmbHNP-108 Freund 2.90% 1.63% 3.08% 5.07% 7.25% 80.07% Industrial Co.

Solidity

The microspheres of the present invention and current commercialmicrospheres/beads were examined for solidity. Solidity looks formissing areas caused by risers or indentations in the surface of themicrosphere or particle. In order to determine the solidity, a cord iswrapped around the microsphere to approximate the area of themicrosphere or particle without convex (indented areas) due to crevicesand risers off the surface. The area of the microsphere or particle isexactly measured as the shadow of the image of the microsphere orparticle in a light path. The area of the microsphere or particle isthen divided by the area inside the cord stretched over themicrospheres' or particles' outer surface. Solidity is calculated inaccordance with International Organization for Standardization (ISO)9276-6 (2008).

A sphere has a solidity of 1. A cube, a triangle (pyramid) or a rodwould also have a solidity of 1. Although a cube and a pyramid havecorners/edges, they do not have surface risers or crevices. Any surfaceindentations or surface bumps would add to the area inside the cord.Thus solidity as a factor is then related to the area associated withthe convexity area of the microsphere as area lost ratio to solidity. Asurface without convexness can be directly coated in layers. Each layerat the start is the base layer and grows uniformly in thickness. Issueswith convexed areas is removing the air, getting the film in the tighterspace uniformly and building the layer in the space to the surface toallow for a uniform outer layer coating thickness. Extra time is spent,smaller droplets sizes of coating spray may be required, moreplasticizer needed to allow the film to bridge without cracking if thecrevice isn't filled and extra coating material is used.

In three dimensions it is also related to the extra volume associatedwith this convexed space. Which either coating fills or bridges overcreating coating stress, imperfections and variation in coating amountneeded to obtain a functional coating. Table 11 shows the solidity ofthe microspheres tested and FIG. 24 is a graph of the solidity of thevarious microspheres tested. The graph demonstrates the lack of solidityof the mannitol microspheres of the present invention (Mannosphere) andthe narrow range of solidity in mannitol microsphere samples. Note theforecasted surface to be coated is consistent with a smoothed surfacewithout risers or crevices for 96% of the particles at a solidity factorof 0.99. A narrow range of solidity for the mannitol microspheres alsoaides in coating thickness consistency and direct coating layering.Maintaining the film surface contour. It is apparent in the SEMs thecrevices in the MCell 400 beads as well as the separation in the NP-108beads made by a similar granulation route would require additionalcoating material to fill these spaces. The SureSpheres and thePharm-a-Sphere beads would loss coating material into the contour of therisers.

TABLE 11 Solidity of the microspheres tested Solidity Solidity SoliditySolidity % > % < % < % < Material Maker Lot 0.99 0.99 > .98 0.98 > .970.97 > .96 Mannospheres SPI Pharma 10/7/11-4 96.7% 2.29% 0.72% 0.17%SureSpheres Colorcon ST502051 14.0% 69.35% 12.37% 2.69% 20/25 MCell 400T Pharmatrans 5100824001  2.5% 8.57% 16.72% 18.65% Sanaq AG Pharm-a-Hanns 08010002   0% 2.96% 16.71% 24.39% Spheres Werner GmbH NP-108Freund 109C-26 56.5% 30.43% 5.80% 2.36% Industrial Co.Convexity

The microspheres of the present invention and current commercialmicrospheres/beads were also examined for convexity. Convexity issimilar to solidity but focuses more on surface smoothness. Here themost accurate measurement is the periphery of the particle. What theapproximation is in this index is the cord length that is drawnsurrounding the particle which is the same cord length as in thesolidity measurement. If the surface is perfectly smooth and withoutcrevices or risers the convexity will be equal to one. Convexity iscalculated in accordance with International Organization forStandardization (ISO) 9276-6 (2008). Table 12 shows the convexity of themicrospheres tested and FIG. 25 is a graph of the convexity of thevarious microspheres tested. Note the forecasted surface to be coated isconsistent with a smoothed surface without risers or crevices for 81% ofthe particles at a convexity of 0.99. It is apparent in the table thatthe effective surface area for coating is lost in area differencebetween the area of a perfectly spherical shape and into either creviceor riser imperfections. The difference at a scale of comparison at 0.99is substantial.

TABLE 12 Convexity of the microspheres tested Convexity ConvexityConvexity Convexity % > % < % < % < Material Maker Lot 0.99 0.99 > 0.980.98 > 0.97 0.97 > 0.96 Mannospheres SPI Pharma 10/7/11-4 81.2% 6.82%4.73% 3.73% SureSpheres Colorcon ST502051 9.0% 75.99% 13.26% 0.90% 20/25MCell 400 T Pharmatrans 5100824001 12.6% 14.68% 16.08% 13.18% Sanaq AGPharm-a- Hanns 08010002 2.3% 2.11% 11.64% 19.19% Spheres Werner GmbHNP-108 Freund 109C-26 52.4% 29.35% 8.70% 6.16% Industrial Co.

Surface Area/Porosity

The microspheres of the present invention and current commercialmicrospheres/beads were also examined for determination of surface areaand porosity. Surface area measurements of the samples were performedusing a Tristar II 3020 surface area analyzer made by Micromeritics(Malvern, Pa.). The analysis gas was nitrogen; the analysis temperaturewas 77.4 K, cold free space was 40.1922 to 41.4298 cm³ measured and thewarm free space was 13.1291 to 13.4346 cm³ measured. The equilibrationinterval was 20 seconds, and the sample density was assumed to be 1.000gm/cm³. The mass of the samples was accurately weighed to approximately2.5 gms. Single point BET was run at a relative pressure of 0.15 to 0.20and extrapolated to zero. Multipoint was done at least two additionalrelative pressure points below the single point measurement relativepressure. Tristar II 3020 V1.04 software was used to calculate thesingle point and multipoint BJH adsorbed and desorbed surface area.

The pore volume measurements were performed on the same instrument usedfor surface area measurement at relative pressure up to 1.0. A sampleaccurately weight of approximately 0.5 gms was used. Ten or morerelative pressure from 0.01 to 1.0 was used. Tristar II 3020 V1.04software was used to calculate the pore volume. Table 13 shows thesurface area and porosity of the various microspheres examined. Datacomparing surface area and pore volume clearly shows the Mannospheremicrospheres of the present invention have less surface area than theSure-Sphere and Pharm-a-Sphere beads in single point and in both the BJHmultipoint adsorption and desorption methods. This lack of pore volumeand lower surface area per gram is due to Mannosphere microspheres'shape being more spherical, and the lack of internal surface compared tothe Sure-Sphere or Pharm-a-Sphere beads or is due to bead size.

TABLE 13 Surface area and Porosity BJH BJH BJH Single point BJHDesorption Adsorption Desorption BET Adsorption Surface Pore PoreSurface Surface Area Volume Volume Sample Area (M2/g) Area (M2/g) (M2/g)(CM3/gm) (CM3/g) Mannosphere 0.04 0.005 0.0498 0.000274 0.000005 BeadsSureSphere Beads 0.26 0.167 0.1844 0.001051 0.000209 Pharm-a-Sphere 0.220.132 0.1433 0.00697 0.000152 Beads

Particle size for each of the microsphere samples was measured by laserparticle size analysis using a Microtrac 5350 made by MicrotracCorporation (Montgomeryville, Pa.). Approximately a one gram sample wasused for the test using the Turbotrac dry feeder at an energy setting of10 and a range of 0.687 to 995.6 μm and a 10 second run time. Thesamples particle size and the samples projected surface area as aperfect was calculated by the Microtrac Flex version 10.4 programsupplied with the analyzer. Data on particle size is listed in the Table14. All samples were assigned a 1.0 gm/ml density to convert volumevalues to grams.

TABLE 14 Particle size and calculated surface area for variousmicrospheres Calculated Surface from Size data Sample M²/gm d(0.1) umd(0.5) um d(0.9) um Mannitol Microsphere 0.0273 133 259 373 EPSuresphere Beads 0.0145 329 413 608 Pharmasphere Beads 0.035 135 175 233

Table 15 compares the size estimate of surface area in themultiparticulate sample to the actual surface area measured by nitrogengas adsorption. Mannosphere microspheres show a much closer predictionof size of beads to surface area of the bead, which is only going to betypical of true spherical beads lacking internal porosity. TheMannosphere microspheres are smaller in particle size (259 μm) toSure-Spheres beads (413 μm). Thus from microsphere size data,Sure-Sphere beads are expected to have a lower surface area. The actualsurface area in Sure-Sphere beads is (0.26/0.04)=6.5 times more thanMannosphere microspheres. Similarly the Pharm-a-Sphere beads are smaller(175 μm), yet they have 5.5 times more surface area than predicted. Theactual to predicted surface area shows how much closer Mannospheremicrospheres have a size predicted surface area for coating.

This data along with the pore volume measurements shows the substantiallack of internal surface as well as the closer match to prefectsphericity by the microspheres of this invention compared to standardmass marketed microspheres or beads. This tighter microsphere size tosurface control allows for a much more accurate use of size to controlboth amount of surface coating per batch but control the surfacelocation as more on the outer surface of the bead versus interior to themicrosphere.

TABLE 15 Actual to Predicted Surface Areas of various microspheresA_(sz), Calculated A_(act), Single Surface from point BET Actual toPredicted Size data Surface Area Surface Area Sample M²/gm (M²/gm)(A_(act)/A_(sz)) Mannitol 0.0273 0.04 1.5 Microspheres EP Sure-SphereBeads 0.0145 0.26 18 (Colorcon) Pharm-a-Sphere Beads 0.035 0.22 6.3(Hanns G Werner)

Dissolution

The microspheres of the present invention and current commercialmicrospheres/beads were also examined for determination of dissolution.The dissolution of microsphere samples was performed in 20 mL glass vialwith cap. (Fisher Scientific, Hampton, N.H.) 10 mL of deionized waterwas added to an accurate weight of approximately 500 mg of microspheres.The vials were place into the holder of the Rotatest Ping-Pong model51500-10 reciprocating shaker (Cole Parmer, Vernon Hills, Ill.) and itsplatform rotated at 300 rpm. After shaking for test time, the sampleswere filtered through pre-weighed 0.45 micron filter paper (NylonMembrane filters, 0.45 micron, 47 mm dia, Cat #7404004, Whatman (FisherScientific, Hampton, N.H.)). The filter paper was dried in aconventional oven at 60° C. and then placed in a suitably sized glassdesiccator (Fisher Scientific, Hampton, N.H.) using fresh drierite(Sigma Aldridge, St. Louis, Mo.). Once cooled the filter paper wasre-weighed to calculate the weight change in mg. Table 16 shows thedissolution of various microspheres. The data shows the limited amountof <0.5% undissolved at both 5 and 10 minutes of testing compared toNP-108 microspheres at 2.0% in 5 minutes and 0.92% in 15 minutes, andSure-Sphere and Pharm-a-Sphere beads with >10% undissolved even at 15minutes of shaking 100% dissolution or solubility is often desirable insituations in which very low dose actives are used in coatings to obtaincomplete recovery of actives.

TABLE 16 Dissolution of various microspheres Dissolution (0.5 g samplein 10 ml Water On Shaker @ 300 rpm) Weight of residue on filter paper @Sample 5 mins 15 mins Mannitol  1.9 mg or 0.38%  1.9 mg or 0.38%microspheres EP NP-108 10.2 mg or 2.04%  4.9 mg or 0.92% (FreundIndustrial Co.) Pharm-a- 61.1 mg or 12.2% 60.7 or 12.1% Sphere (Hanns GWerner) Sure-Spheres  100 mg or 20% 98.1 or 19.6% (Colorcon)

Oil Adsorption

The microspheres of the present invention and current commercialmicrospheres/beads were also examined for oil adsorption. 1.00 g of eachmicrosphere sample was accurately weighed. The sample was added to amortar and pestle and 0.02 g of Light Mineral Oil, USP/NF (SigmaAldrige, St. Louis, Mo.) was added drop-wise (Transfer pipet,disposable, standard, polyethylene, one-piece, single squeeze draws upto 3.2 mL, length 5.875 in., capacity 7.7 mL; Fisher Scientific,Hampton, N.H.). The oil was thoroughly incorporated into the sample bylightly mixing, but not crushing in the mortar and pestle (Mortar andPestle: Coors, USA. Cat #60319, Fisher Scientific, Hampton, N.H.) for 3minutes. The samples were visually observed to determine is the samplewas free flowing or sticky/agglomerated. Table 17 shows the oiladsorption for the various microspheres. None of the samples tested wasable to adsorb 2% oil and remain as free flowing beads. All of thesebeads are constructed to have minimum oil adsorption capacity.

TABLE 17 Oil Adsorption of various microspheres Oil Adsorption CapacityObservation @ Sample (1.00 g) 0.1 g Mineral Oil 0.02 g Mineral OilMannitol Microspheres EP Sticky powder Sticky powder NP-108 (FreundIndustrial Co.) Sticky powder Sticky powder Pharm-a-Sphere (Hanns GSticky powder Sticky powder Werner) Sure-Spheres (Colorcon) Stickypowder Sticky powder

Example 3

Erythritol EP (Baolingbao Biology Co., LTD., China) was added to aTornado Spin Disc (Gold Metal Cincinnati Ohio). The units spin head washeated to ˜160° C. while spinning at 3400 RPM and made microspheres witha PSD of d(0.1)=131 μm, a d(0.5)=262 μm and a d(0.9)=371 μm. The sizedistribution ratio is 2.8 to 1 for this run. The DSC of these beadsshows a single and sharp melt peak at 121.6° C. with a heat of fusion of273.1 J/g. A pure crystalline erythritol melt range of 199° C. to 121°C. is expected and thus crystal structure of formed microsphere is astandard and highest energy erythritol polymorph.

1-29. (canceled)
 30. A microsphere comprising a core material, whereinthe microsphere has a circularity greater than 0.98 and an aspect ratiogreater than 0.98.
 31. The microsphere of claim 30, wherein themicrosphere has a mean particle size from about 10 μm to about 500 μm.32. The microsphere of claim 31, wherein the microsphere has a meanparticle size from about 10 μm to about 20 μm.
 33. The microsphere ofclaim 32, wherein the microsphere has a moisture content of 0.5% orless.
 34. The microsphere of claim 30, wherein the microsphere has aparticle size distribution of 2.8 or less.
 35. The microsphere of claim34, wherein the microsphere has a particle size distribution of 2.0 orless.
 36. The microsphere of claim 30, wherein the microsphere has asurface with ridges 10 μm or less.
 37. The microsphere of claim 30,wherein the microsphere has a skeletal density from about 1.4595 g/cc toabout 1.4651 g/cc.
 38. The microsphere of claim 30, wherein themicrosphere has a moisture content of 0.5% or less.
 39. The microsphereof claim 30, wherein the microsphere is water soluble.
 40. Themicrosphere of claim 30, wherein the microsphere comprises a single corematerial.
 41. The microsphere of claim 40, wherein the single corematerial is mannitol.
 42. The microsphere of claim 30, wherein themicrosphere comprises a crystalline core.
 43. The microsphere of claim30, wherein the microsphere further comprises an active pharmaceuticalingredient.
 44. The microsphere of claim 30, wherein the core materialis a polyol.
 45. The microsphere of claim 44, wherein the polyol ismannitol.
 46. The microsphere of claim 30, wherein the microsphere lacksporosity.
 47. The microsphere of claim 30, wherein the microsphere lackinternal voids.
 48. A composition comprising the microsphere of claim30.
 49. The composition of claim 48 further comprising an activepharmaceutical ingredient.